SYMPOSIUM ONINSOLID TUMORS MALIGNANT MELANOMA THE 21ST CENTURY

Malignant Melanoma in the 21st Century, Part 2: Staging, Prognosis, and Treatment SVETOMIR N. MARKOVIC, MD, PHD; LORI A. ERICKSON, MD; RAVI D. RAO, MBBS; ROGER H. WEENIG, MD; BARBARA A. POCKAJ, MD; ADITYA BARDIA, MD; CELINE M. VACHON, PHD; STEVEN E. SCHILD, MD; ROBERT R. MCWILLIAMS, MD; JENNIFER L. HAND, MD; SUSAN D. LAMAN, MD; LISA A. KOTTSCHADE, RN; WILLIAM J. MAPLES, MD; MARK R. PITTELKOW, MD; JOSE S. PULIDO, MD, MS, MPH, MBA; J. DOUGLAS CAMERON, MD; AND EDWARD T. CREAGAN, MD, FOR THE MELANOMA STUDY GROUP OF THE MAYO CLINIC CANCER CENTER Critical to the clinical management of a patient with malignant melanoma is an understanding of its natural history. As with most malignant disorders, prognosis is highly dependent on the clinical stage (extent of tumor burden) at the time of diagnosis. The patient’s clinical stage at diagnosis dictates selection of therapy. We review the state of the art in melanoma staging, prognosis, and therapy. Substantial progress has been made in this regard during the past 2 decades. This progress is primarily reflected in the development of sentinel lymph node biopsies as a means of reducing the morbidity associated with regional lymph node dissection, increased understanding of the role of neoangiogenesis in the natural history of melanoma and its potential as a treatment target, and emergence of innovative multimodal therapeutic strategies, resulting in significant objective response rates in a disease commonly believed to be drug resistant. Although much work remains to be done to improve the survival of patients with melanoma, clinically meaningful results seem within reach.

Mayo Clin Proc. 2007;82(4):490-513 AJCC = American Joint Committee on Cancer; CI = confidence interval; CT = computed tomography; CTLA4 = cytotoxic T-lymphocyte–associated protein 4; CVD = cisplatin, vinblastine, and dacarbazine; ECOG = Eastern Cooperative Oncology Group; ELND = elective lymph node dissection; FDA = Food and Drug Administration; GM-CSF = granulocyte-macrophage colony-stimulating factor; IL = interleukin; LDH = lactate dehydrogenase; MART = melanoma antigen recognized by T cells; PACV = polyvalent allogeneic irradiated whole-cell vaccine; PET = positron emission tomography; RR = relative risk; RT-PCR = reverse transcriptase–polymerase chain reaction; SLN = sentinel lymph node

I

n part 1 of “Malignant Melanoma in the 21st Century,”1 we discussed the epidemiology, risk factors, screening, prevention, and diagnosis of malignant melanoma. In this second part, we review the state of the art in melanoma staging, prognosis, and therapy. Substantial progress has been made in this regard during the past 2 decades. This progress is primarily reflected in the development of sentinel lymph node (SLN) biopsies as a means of reducing the morbidity associated with regional lymph node dissection, increased understanding of the role of neoangiogenesis in the natural history of melanoma and its potential as a treatment target, and emergence of innovative multimodal therapeutic strategies, resulting in significant objective response rates in a disease commonly believed to be drug resistant. 490

Mayo Clin Proc.

•

PROGNOSTIC FEATURES AND PATHOLOGIC STAGING The histologic evaluation of melanoma provides critical staging information. The American Joint Committee on Cancer (AJCC) Melanoma Staging Committee, which comprises major melanoma centers in the United States, Europe, and Australia and national cancer cooperative groups, studied 17,600 melanomas from patients with clinical, pathologic, and follow-up information.2 Cox proportional hazards regression was used to study factors that predict melanoma-specific survival rates.2 Results of this evidence-based study were incorporated into the 2002 AJCC melanoma TNM staging classification (Tables 1 and 2).3,4 The 2002 AJCC staging system incorporates pathologic “microstaging attributes,” including Breslow depth, Clark level, and ulceration.3 Tumor thickness and ulceration were the most powerful predictors of survival.2 The level of invasion had significance only in thin (≤1.0 mm) melanomas.2 These and other factors are discussed in the following sections. DEPTH OF INVASION The depth of invasion is the most important histologic prognostic parameter in evaluating the primary tumor. The importance of this factor has been recognized for decades From the Division of Hematology (S.N.M.), Department of Oncology (S.N.M., R.D.R., R.R.M., L.A.K., E.T.C.), Department of Immunology (S.N.M.), Department of Laboratory Medicine and Pathology (L.A.E.), Department of Dermatology (R.H.W., J.L.H., M.R.P.), Department of Internal Medicine (A.B.), Department of Health Sciences Research (C.M.V.), and Department of Ophthalmology (J.S.P., J.D.C.), College of Medicine, Mayo Clinic, Rochester, Minn; Department of Surgery (B.A.P.), Department of Radiation Oncology (S.E.S.), and Department of Dermatology (S.D.L.), College of Medicine, Mayo Clinic, Scottsdale, Ariz; and Division of Hematology/Oncology (W.J.M.), College of Medicine, Mayo Clinic, Jacksonville, Fla. A complete list of the current members of the Melanoma Study Group of the Mayo Clinic Cancer Center appears in reference 1. Address correspondence to Svetomir N. Markovic, MD, PhD, Division of Hematology, College of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905. Individual reprints of this article and a bound reprint of the entire Symposium on Solid Tumors will be available for purchase from our Web site www.mayoclinicproceedings.com. © 2007 Mayo Foundation for Medical Education and Research

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

MALIGNANT MELANOMA IN THE 21ST CENTURY

TABLE 1. American Joint Committee on Cancer 2002 Melanoma TNM Classification*3,4 Symbol TX

Description

Suffix

T0 Tis T1

Primary tumor cannot be assessed (ie, shave biopsy or regressed melanoma) No evidence of primary tumor Melanoma in situ ≤1.0 mm

T2

1.01-2.00 mm

T3

2.01-4.0 mm

T4

>4.0 mm

N1

1 lymph node

N2

2-3 lymph nodes

N3

≥4 metastatic lymph nodes, matted lymph nodes, or combinations of in-transit metastasis or satellite(s) and metastatic lymph node(s) Distant skin, subcutis, or lymph node metastases Lung metastases All other visceral metastases Any distant metastases

M1a M1b M1c

a: without ulceration and level II or III b: with ulceration or level IV or V a: without ulceration b: with ulceration a: without ulceration b: with ulceration a: without ulceration b: with ulceration a: micrometastasis† b: macrometastasis‡ a: micrometastasis† b: macrometastasis‡ c: in-transit metastasis or satellite(s) without metastatic nodes

Normal LDH level Normal LDH level Normal LDH level Elevated LDH level

*LDH = lactate dehydrogenase. †Micrometastases are diagnosed after elective or sentinel lymphadenectomy. ‡Macrometastases are defined as clinically detectable lymph node metastases confirmed by therapeutic lymphadenectomy or when any lymph node metastasis exhibits gross extracapsular extension.

and evaluated both qualitatively and quantitatively. In 1953, Allen and Spitz4 stated that patients with superficial tumors had a greater chance of survival than patients with deeply invasive tumors. Others also recognized depth of invasion as an important prognostic factor in malignant melanoma decades ago.5-9 A variety of terms have been used to denote qualitative anatomic levels of invasion, including stages,7 groups,8 and levels9 of invasion. The system used today was described by Clark et al.9 In level I malignant melanoma, all tumor cells are above the basement membrane (malignant melanoma in situ). Level II tumors invade into the papillary dermis, which extends around skin appendages.9 Level III tumors fill and expand the papillary dermis. Importantly, isolated tumor cells between collagen bundles in the upper reticular dermis at the base of level III tumors are still considered level III.9 Tumors that invade into the reticular dermis are level IV, and those that invade into the subcutaneous adipose tissue are level V. Stratification of 208 patients with invasive melanoma by Clark level showed that 8.3% with level II, 35.2% with level III, 46.1% with level IV, and 52% with level V tumors died of disease.9 In 1970, Dr Alexander Breslow10 provided quantitative measurement of the depth of invasion by measuring the tumor thickness with an ocular micrometer. The measurement (in millimeters) is made from the top of the granular layer of the epidermis to the deepest melanoma cell. If a Mayo Clin Proc.

•

tumor is ulcerated, the measurement is made from the highest viable melanoma cell to the deepest tumor cell. Adventitial dermal invasion is not measured unless it is the only site of invasion. Then, the measurement is made from TABLE 2. Pathologic Stage Grouping and Survival3,4 Pathologic stage

April 2007;82(4):490-513

0 IA IB

Tumor

IIC IIIA

Tis T1a T1b T2a T2b T3a T3b T4a T4b T1-4a

IIIB

T1-4b

IIA IIB

T1-4a IIIC

T1-4a/b T1-4b

IV

Any T Any T

•

Lymph nodes

Distant metastases

10-y survival rate (%)

N0 N0 N0 N0 N0 N0 N0 N0 N0 N1a N2a N1a N2a N1b N2b N2c N1b N2b N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1a M1b M1c

100 88 83 79 64 64 50 54 32 63 57 38 36 48 39 … 24 15 18 16 3 6

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

491

MALIGNANT MELANOMA IN THE 21ST CENTURY

the inner luminal surface of the eccrine gland or duct or inner aspect of the outer root sheath epithelium of the hair follicle.10 Breslow depth is a continuous variable and is the most important prognostic factor in the primary cutaneous melanoma.2,10-26 Clark level remains an independent prognostic factor for thin melanomas.2,27 In the 1997 TNM staging system, Clark level was the primary determinant of T staging, with Breslow thickness a second prognostic factor of T stage. In the 2002 AJCC staging classification, Clark level is used only in T1 melanomas.3 Tumor thickness as measured by the Breslow technique is the primary determinant of T staging.3 Thin melanomas are now defined by many as those with a depth of invasion of 1.0 mm or less. Staging thresholds of depth have changed from 0.75, 1.50, and 4.0 mm in the 1997 TNM version to 1.0, 2.0, and 4.0 mm in the 2002 TNM version.3,24,28 Although these breakpoints are used in staging classifications, Breslow depth is a continuous variable. ULCERATION Ulceration is defined in the 2002 AJCC staging classification as the absence of an intact epidermis overlying a major portion of the primary melanoma based on microscopic examination of the histologic sections.3 Ulceration was second only to tumor thickness as the most powerful independent predictor of survival in 17,600 cases.2 Although ulceration was an independent predictive factor, it correlated with tumor thickness. Ulceration was identified in only 6% of thin (≤1.0 mm) melanomas but was noted in 63% of thick (>4.0 mm) tumors.2 Patients with ulcerated melanomas had the same survival rate as those with nonulcerated tumors of the next greater thickness category.2 MICROSATELLITES, SATELLITES, AND IN-TRANSIT METASTASES Historically, satellites were microscopic or macroscopic discontinuous foci of tumor located within 5 cm of the primary tumor, and in-transit metastases were discontinuous foci located more than 5 cm from the primary tumor. The clinical behavior of satellites or in-transit disease was believed to not impart as poor a prognosis as lymph node metastases. Clinical or microscopic satellites around a primary melanoma and in-transit metastases are considered intralymphatic metastases and portend a poor prognosis.3,29-32 Satellites and in-transit metastases are considered the same clinically, and no survival difference is apparent between these 2 groups.24 They are both classified as N2c in the absence of nodal metastases because they both have a prognosis similar to multiple lymph node metastases.3 Patients with both satellites or in-transit metastases and nodal metastases have a worse prognosis than patients who have either satellites or in-transit metastases or nodal metastases alone.3,24 When both satellites or in-transit disease and 492

Mayo Clin Proc.

•

lymph node metastases are diagnosed in the same patient, they are classified as N3 regardless of the number of involved lymph nodes.3 PATHOLOGIC STAGING OF LYMPH NODES Regional lymph node status is a significant prognostic feature of malignant melanoma.2,33 Historically, the size of the lymph node metastases was believed to be important, but analysis of the data demonstrated that the number of lymph nodes was the most important feature, followed by the tumor burden within the lymph node. If 1 node is involved, the classification is N1; if 2 to 3 nodes are involved, the classification is N2; and if 4 or more metastatic nodes, matted nodes, or in-transit metastases or satellites with metastatic node(s) are involved, the classification is N3. The presence of an ulcerated tumor in the setting of positive lymph nodes carries a grave prognosis; therefore, an ulcerated melanoma in association with any number of lymph node metastases is classified as N3. N1 and N2 are further classified as micrometastasis, which is diagnosed histologically, and macrometastasis, which is defined as clinically detectable nodal metastases confirmed therapeutically.34 Patients who have stage III disease are a heterogeneous group with a 5-year survival rate of 13% for a patient with an ulcerated melanoma with 4 or more macroscopically positive lymph nodes to 69% for a patient with a nonulcerated melanoma and 1 microscopically positive lymph node. Sentinel lymph nodes for melanoma are generally evaluated both histologically and with immunostains. Lymph nodes that are found to have disease identified by immunostains only and are not seen with routine hematoxylin-eosin staining are considered N0. A special designation of N0 (immunohistochemically positive) is preferred, and this information may be important for further staging criteria in the future. Capsular nevi need to be differentiated from metastatic melanoma. The location of the nevic nests in the capsule and the benign cytomorphologic findings of the cells are helpful in differentiating these entities. Immunostains are used to increase the detection of melanoma micrometastases in SLNs. Recently, a study of 217 lymph nodes from patients with no history of melanoma showed individual Melan-A or MART-1 (melanoma antigen recognized by T cells) immunoperoxidase cells in the parenchyma of 2.4% and 5.1% of lymph nodes, respectively.35 Thus, the finding of Melan-A– or MART-1–positive cells without corresponding cytologic atypia or hematoxylineosin findings should be interpreted with caution.35 DISTANT METASTASES Distant metastases in the skin, subcutaneous tissue, or distant lymph nodes are classified as M1a. Metastases to the

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

MALIGNANT MELANOMA IN THE 21ST CENTURY

lung are M1b, and those to other visceral sites are M1c. A significant difference is apparent in 1-year survival rates between patients with skin, subcutaneous, distant lymph nodes, and lung metastases vs all other sites.34 ADDITIONAL PROGNOSTIC FACTORS IN THE PRIMARY TUMOR Although not incorporated into the current AJCC staging classification, several other prognostic factors are often included in pathology reports of primary melanomas because they have been shown to have prognostic significance in some studies. These factors include radial and vertical growth phases,9,14,19,36-45 mitotic rate,14,19,46-54 regression,14,19,45,55-61 angiolymphatic invasion,42,54,62,63 angiotropism,64-66 perineural invasion, and tumor-infiltrating lymphocytes.14,67-70 GROWTH PHASE The concept of radial and vertical growth phases dates back to the work of Clark et al,9 who recognized that most melanomas develop through steps of tumor progression. Radial growth phase describes the growth of melanoma within the epidermis and along the dermal-epidermal junction. Tumors that invade into the papillary dermis are also considered to have only a radial growth phase if they show no dermal mitotic activity, are nontumorigenic, and are generally Clark level II. All malignant melanomas, except nodular melanomas, have a radial growth phase because they are thought to evolve in a stepwise fashion.36 Tumors in the radial growth phase of invasion are generally not associated with metastases.36 Vertical growth phase melanomas are tumorigenic or have dermal mitotic activity. Early vertical growth phase melanomas have a dominant tumor nest in the dermis that is larger than any within the epidermis or surrounding dermis.37 Growth phases were evaluated in 211 patients with invasive cutaneous melanomas, including 65 with radial growth phase only and 146 with vertical growth phase.38 The disease-free survival rate at 5 years was 63.7% for vertical growth phase tumors and 100% for radial growth phase only tumors.38 A model that predicted survival in stage I melanoma based on tumor progression using multivariable logistic regression showed that the 8-year survival rate of patients with vertical growth phase melanomas was 71.2%, whereas 122 patients with invasive radial growth phase only tumors had no metastases.14 In another study, all 161 melanomas with pure radial growth phase were followed up for a median of 13.7 years, and none were associated with metastases.39 A case-control study evaluated the relevance of vertical growth phase in Clark level II melanomas that were 0.76 mm deep or less.40 Vertical growth phase was found to be the only statistically significant Mayo Clin Proc.

•

prognostic factor. The authors suggested that vertical growth phase evaluation be added to the melanoma histologic report for level II superficial spreading melanomas.40 In another recent study, 77 patients with thin (<1 mm) cutaneous melanomas underwent SLN biopsy, and 6 patients were found to have positive sentinel nodes.41 Vertical growth phase (P=.002), ulceration (P=.019), and high mitotic rate (P=.008) were positively correlated with metastatic disease.41 Although most melanomas that lack vertical growth phase are not associated with metastases, melanomas without identified vertical growth phase have metastasized.14,71 Additionally, most malignant melanomas with vertical growth phase are not associated with metastases.71 The presence of regression also appears to be an important feature in patients with radial growth phase melanomas associated with metastatic disease.42 Melanomas with epithelioid cells in vertical growth phase tend to have a worse prognosis than those with spindle cells.43,44 MITOTIC RATE Mitotic rate is tabulated as mitoses per square millimeter in the dermal part of the tumor in which most mitoses are identified, as recommended in the 1982 revision of the 1972 Sydney classification of malignant melanoma.72 Although ulceration is considered the most important prognostic factor after Breslow thickness for localized cutaneous melanoma, many studies have shown that mitotic rate is a significant prognostic factor.46-53 In a population-based series of 650 consecutive invasive cutaneous melanomas from the Connecticut tumor registry, tumor thickness and mitotic activity were independent prognostic factors in multivariate regression analysis. After adjustment for mitotic rate, ulceration was no longer significant. When mitotic rate was excluded, ulceration then became an independent prognostic factor. When mitotic rate was excluded, the model showed a relative risk (RR) with ulceration of 2.4 (95% confidence interval [CI], 1.1-5.1). When ulceration was excluded, the model with only a mitotic rate showed an RR of 14.5 (95% CI, 3.9-53.7). Regression analysis, including both ulceration and mitotic rate, showed an RR of 11.6 (95% CI, 3.0-44.6) for mitotic rate and 1.7 (95% CI, 0.8-3.6) for ulceration. In this study, the authors concluded that mitotic rate is a more important prognostic factor than ulceration.46 A study of 3661 patients with melanoma from the Sydney Melanoma Unit showed that a mitotic rate of 0 per square millimeter was associated with better survival than those with 1 mitosis per square millimeter, but no significant survival differences were noted for stepwise increases from 1 to 2, 2 to 3, 3 to 4, and 4 to 5 mitoses per square millimeter. Although tumor thickness, ulceration, and mi-

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

493

MALIGNANT MELANOMA IN THE 21ST CENTURY

totic rate were closely correlated, Cox regression analysis indicated that mitotic rate was a highly significant independent prognostic factor, second only to tumor thickness. The authors concluded that mitotic rate has the potential to improve the accuracy of melanoma staging and to more rigidly define risk categories for patients entering clinical trials.47 Mitotic rate has also been shown to be a significant independent predictor of clinical outcome in patients with thick49 and thin41,50-54 melanomas. The clinical outcome of 140 patients with thick (>3 mm) stage I cutaneous melanomas was evaluated retrospectively to analyze the prognostic value of a series of clinicopathologic parameters on survival.49 The overall disease-free survival rates at 5 and 10 years were 55.3% and 47.7%, respectively. Multivariate analysis with a Cox proportional hazards model showed that tumor thickness, infiltrating invasive front of the tumor, ulceration, and mitotic rate were significant independent prognostic factors.49 Recent studies have shown mitotic rate to be a significant predictor of lymph node metastases in patients with thin melanomas.41,50-54 A prospective evaluation of 884 patients with thin invasive melanomas showed that growth phase, mitotic rate, and male sex were important prognostic factors and helped identify subgroups at risk for metastases.50 REGRESSION Malignant melanomas are known to show regression. Histologically, regression is characterized by the absence of melanoma in the epidermis and dermis flanked on one or both sides by melanoma. The dermis in this area shows delicate fibroplasia, scattered lymphocytes, and melanophages. Complete regression is uncommon in malignant melanomas but may explain some cases of metastatic melanoma with an indeterminate primary site.73 Regression has also been identified in cases of malignant melanoma in situ and metastatic disease.60 Although not all studies have found regression to be a statistically significant predictor of survival,55,67,74-76 many studies have found regression to be associated with a worse prognosis and decreased survival.14,19,42,45,56-58 Melanomas with extensive (>75%) or complete regression appear to have a worse prognosis than those with lesser degrees of regression.45,56,60,61 Regression is thought to be particularly important in thin melanomas.42,45,56-60 A case-control study showed that extensive regression was present in 42% of patients with thin (<1 mm) melanomas associated with metastases but only in 5% of matched controls.60 A review of patients with thin (<0.76 mm) melanomas showed that severe histologic regression was present in 40% of primary lesions that metastasized and in only 17% of lesions that did not.61 Another study that evaluated thin malignant melanomas (≤0.76 mm) found 494

Mayo Clin Proc.

•

that 30 of 103 tumors showed partial regression. Six of the 30 patients developed metastases and died.56 These 6 patients had more than 75% regression of their primary tumors.56 None of the 73 patients with thin melanomas without regression had metastases.56 A study evaluating nontumorigenic radial growth phase and tumorigenic vertical growth phase melanomas showed that patients with melanoma without regression and without the tumorigenic vertical growth phase can be given reasonable assurance of survival.45 A retrospective population-based study of 1716 cutaneous melanomas that were 1 mm or smaller identified metastases in 67 cases.42 Thirteen of these 67 melanomas were level II. Eight of the 13 patients with level II melanoma with metastasis were found to have another primary cutaneous melanoma with at least level III invasion before the metastases occurred. All 5 of the remaining tumors showed regression. The authors concluded that metastasis from level II melanoma without regression is rare.42 TUMOR-INFILTRATING LYMPHOCYTES Tumor-infiltrating lymphocytes have been found to have prognostic significance.14,67-70 Tumor-infiltrating lymphocytes are currently defined as brisk, nonbrisk, and absent. A study of 72 patients with clinical stage I melanoma of intermediate thickness (1.51-3.99 mm) and at least 5 years of follow-up found that low mitotic rate and an infiltrative lymphocytic response were associated with favorable survival.68 In a model that predicted survival of patients with clinical stage I melanoma, 23 features were evaluated by multivariate analysis, and 6 were found to be independent prognostic factors, including tumor-infiltrating lymphocytes, mitotic rate, tumor thickness, anatomic site of primary tumor, sex, and regression.14 The prognostic value of tumor-infiltrating lymphocytes in the vertical growth phase of 285 primary cutaneous stage I or II melanomas was evaluated.67 The 5- and 10-year survival rates for patients with vertical growth phase melanoma were 77% and 55% for those with a brisk infiltrate, 53% and 45% for those with a nonbrisk infiltrate, and 37% and 27% for those with absent tumor-infiltrating lymphocytes, respectively. Multivariate analysis of thickness, mitotic rate, and tumor-infiltrating lymphocytes showed that thickness and tumorinfiltrating lymphocytes were significant and independent histologic prognostic factors. The authors concluded that when tumor-infiltrating lymphocytes are strictly defined, they have a strong predictive value in vertical growth phase melanomas.67 ANGIOLYMPHATIC INVASION AND ANGIOTROPISM The prognostic significance of angiolymphatic invasion is difficult to document because it has a close relationship

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

MALIGNANT MELANOMA IN THE 21ST CENTURY

with tumor thickness,63 but it has been found to have independent prognostic significance in some studies.54,62,63 Vascular invasion was identified in 15 of 102 nodular melanomas and was significantly associated with tumor thickness, histologic diameter, ulceration, lymph node involvement, and distant metastases.63 Vascular invasion had independent prognostic significance in both univariate and multivariate analyses.63 A retrospective study of 215 patients with stage I and II melanoma showed that 46 patients had positive SLNs.54 Risk factors for node involvement were ulceration, high mitotic rate, tumor angiolymphatic invasion, and microsatellites. Patients with tumors thicker than 1.0 mm with none of these risk factors had only a 14% risk of metastases.54 A study of 329 patients with thick (>4 mm) melanomas showed that, when lymph node status was accounted for, tumor thickness, vascular involvement, and ulceration remained independent predictors of survival by multivariate analysis.62 Angiotropism has been identified in cutaneous melanoma and shown to be a prognostic factor that predicts risk of metastasis.64-66,77 An angiotumoral complex was described in which tumor cells occupy a pericytic location along the endothelium of microvessels without intravasion.64-66 This pericyte angiotropism may be a marker of extravascular migration of tumor cells similar to that proposed for glioma migration.66 MELANOMA CLINICAL STAGING The melanoma staging criteria were updated and made official with the publication of the 6th edition of the AJCC Cancer Staging Manual in 2002.78 The following section describes the various stages of melanoma and the median survival associated with each stage. The new AJCC staging criteria for melanoma are divided into 4 distinct stages.78 Localized melanoma is classified under stage I and stage II, whereas stage III melanoma includes regional metastases, and stage IV encompasses distant metastases. Each stage uses the TNM classifications when determining stage of disease.78 Balch et al3 validated the staging system of malignant melanoma on the basis of their results from analysis of a major database of prognostic factors of more than 17,600 patients from 13 cancer centers and organizations. DEFINITIONS Stage I. Stage I cancer is diagnosed in patients who have primary lesions that are 1 mm or less in thickness with no evidence of metastasis. Stage IA (T1a N0 M0) includes patients whose primary lesions are 1 mm or less in thickness with no ulceration and do not invade the reticular dermis or subcutaneous fat (Clark level
•

Stage IB (T1b or T2a N0 M0) includes patients whose primary lesions are 1 mm or less in thickness and have ulceration or invasion to Clark level IV or V (T1b) or patients whose primary lesions are 1.01 to 2.0 mm in thickness without ulceration. Stage II. Stage II cancer is diagnosed in patients with thicker primary lesions, without evidence of metastasis. Stage IIA (T2b or T3a N0 M0) includes patients whose primary lesions are 1.01 to 2.00 mm thick and have ulceration (T2b) or patients whose primary lesions are 2.01 to 4.00 mm thick without ulceration (T3a). Stage IIB (T3b or T4a N0 M0) includes patients whose primary lesions are 2.01 to 4.00 mm thick and have ulceration (T3b) or patients whose primary lesions are more than 4.00 mm thick without ulceration (T4a). Stage IIC (T4b N0 M0) includes patients whose primary lesions are more than 4.0 mm thick and have ulceration. Stage III. Stage III cancer is diagnosed when the melanoma spreads to the regional lymph nodes and/or an intransit or satellite metastasis is present. Stage IIIA (T1-4a N1a or N2a M0) includes patients whose primary lesions are of any depth without ulceration and who have 1 to 3 nodes involved with microscopic disease as discovered after a sentinel or elective lymphadenectomy. Stage IIIB (T1-4b N1a or N2a M0, T1-4a N1b or N2b M0, or T1-4a/b N2c M0) includes patients whose primary lesions are of any depth with ulceration and who have 1 to 3 nodes involved with microscopic disease. or Patients whose primary lesions are of any depth without ulceration and who have 1 to 3 nodes involved with macroscopic disease as discovered on clinical examination and confirmed by therapeutic lymphadenectomy or when nodal metastasis displays gross extracapsular extension. or Patients whose primary lesions are of any depth with or without ulceration and who have in-transit or satellite metastasis without the presence of metastatic lymph nodes. Stage IIIC (T1-4b N1b M0, T1-4b N2b M0, or any T N3 M0) includes patients whose primary lesions are of any depth with ulceration and who have 1 to 3 macroscopically involved lymph nodes (N1b or N2b). or Patients with any depth of tumor with or without ulceration and 4 or more metastatic nodes, matted nodes, or intransit or satellite metastasis with the presence of metastatic node(s) (N3). Stage IV. Stage IV cancer is diagnosed when the melanoma spreads to distant sites, including the skin, subcutaneous tissue, lymph nodes, and organs. The 3 levels of division of stage IV disease are based on the M status. M1a (any T, N) includes patients with any depth of tumor, with or without ulceration, with or without nodal involvement, and with distant metastasis limited to distant

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

495

MALIGNANT MELANOMA IN THE 21ST CENTURY

TABLE 3. Surgical Management of Melanoma Tumor thickness (mm)

Radius of excision (cm)

In situ ≤1.0

0.3-0.5 1

1.1-2.0 2.1-4.0 >4.0

1-2 2 2

Options for lymph nodes Observation Selective sentinel lymph node biopsy, observation Sentinel lymph node biopsy, observation, elective lymph node dissection Sentinel lymph node biopsy, observation, elective lymph node dissection

skin, subcutaneous tissue, or lymph nodes and a normal lactate dehydrogenase (LDH) level. M1b (any T, N) includes patients with these same criteria but who also have metastasis to the lungs and a normal LDH level. M1c (any T, N) includes patients with these same criteria but who also have metastasis to any other visceral site and a normal LDH level or any patient with distant metastasis regardless of the site but with an elevated LDH level. SURVIVAL Balch et al3 described the survival rates for 17,600 of 30,450 patients in the AJCC Melanoma Database who had information available for all the factors required for the proposed TNM classification and stage grouping (Table 2). SURGICAL THERAPY The most definitive therapeutic intervention in the management of malignant melanoma is primary surgical excision. Most patients with primary tumors of less than 1 mm thickness have a low risk of locoregional or systemic spread. Therefore, preoperative evaluation for occult visceral metastases is usually not required in this population. For patients with a melanoma thicker than 1 mm, a chest xray film and baseline liver function tests may be routinely performed, although the yield is low in the absence of symptoms. For patients with stage III disease, further work-up with computed tomography (CT) needs to be performed as clinically indicated. Clinical symptoms should dictate further work-up because extensive imaging studies in the absence of symptoms have a low yield.79,80 Positron emission tomography (PET) has no role in patients with clinical stage I or II disease; the sensitivity of identifying involved lymph nodes with PET is only 20%.81 However, PET may be helpful in evaluating patients at high risk for metastatic disease (eg, stage IIC, stage III, or stage IV disease) before planned surgical intervention. One study has shown that findings on preoperative PET (eg, detection 496

Mayo Clin Proc.

•

of occult metastases) result in changes in therapy plans in only a few patients.82 EXTENT OF EXCISION Thicker tumors have a higher rate of local recurrences and hence require wider surgical margins when excisions are performed. The width of the margins required for any given thickness of tumor has been studied in several randomized surgical trials. A number of trials have been performed to determine the optimal surgical resection margin for melanomas of various depths. The World Health Organization Melanoma Program randomized patients with melanomas more than 2 mm thick to excision margins of 1 or 3 cm. Clinical outcomes (regional and distant metastatic rates) were comparable in both arms; however, 3 patients in the 1cm margin group (all of whom had tumors >1 mm) had local recurrences. The conclusions of that study are that for patients with thin melanomas (ie, <1 mm), a margin of 1 cm is adequate.83 The Intergroup Melanoma Trial randomized patients with intermediate-thickness melanoma (1-4 mm) to be treated with 2- or 4-cm margins. They concluded that 2- and 4-cm margins were equally effective in achieving comparable rates of local control and survival. The local recurrence rate was influenced by melanoma thickness (2.3% for 1.1- to 2.0-mm thickness, 4.2% for 2.1- to 3.0mm thickness, and 11.7% for 3.01- to 4.0-mm thickness) and presence or absence of ulceration (10.6% vs 1.5%). On follow-up of 10 years, no difference in survival or local recurrence rates was found between patients who underwent excision with a 2- or 4-cm margin.12 Local recurrence rates were related to the presence of ulceration and site of the melanoma (proximal extremity, 1.1%; trunk, 3.1%; distal extremity, 5.3%; and head and neck, 9.4%).3 No randomized trials have evaluated adequate margins for thick (>4 mm) melanomas. The largest retrospective review to address this issue evaluated outcomes in patients with thick melanomas and detected no differences in outcomes (local recurrences and overall survival) between patients with tumor margins of less or greater than 2 cm.84 The recommendations based on tumor thickness are summarized in Table 3. For locations in which a 2-cm section is impossible, such as in the head and neck area, a negative margin resulting in a reasonable cosmetic result is thought to be acceptable. Removing the fascia is not thought to be necessary and does not improve local recurrence or survival rates. In special circumstances, use of a Mohs resection can only be considered exploratory.85 EVALUATION OF THE LYMPH NODES In malignant melanoma, as with most solid tumors, the status of lymph nodes is a powerful predictor of recurrence and survival. The overall survival rate of patients with

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

MALIGNANT MELANOMA IN THE 21ST CENTURY

lymph node metastases (stage III) is between 13% and 69%.86,87 The risk of lymph nodal involvement correlates with thickness of the primary lesion and presence of ulceration. The pattern of metastases for melanoma was believed to initially involve the regional lymph nodes, and removal of the regional lymph nodes was believed to have the potential to cure patients with clinically occult lymph nodes. This belief led to the practice of routine elective lymph node dissection (ELND) in all patients who were deemed to have a high risk of regional spread (ie, >1-mmthick melanomas). Retrospective analyses performed at Duke University, at the Sidney Melanoma Unit, and by Charles Balch suggested a survival advantage for ELND in patients with intermediate-thickness melanoma.88-90 Even though ELND was suggested to impart a survival advantage, this advantage was in the most morbid portion of the surgery, and ELND can result in temporary or chronic lymphedema, especially in the lower extremities, seroma formation, infection, and chronic pain.87 Several prospective randomized trials compared ELND with observation in patients with intermediate-thickness melanomas, and all demonstrated a lack of benefit with routine ELND in patients with intermediate-thickness melanoma.12,91-93 Unfortunately, these trials were underpowered because only 20% of patients with an intermediate-thickness melanoma had lymph node metastases at the time of ELND, and 80% did not benefit from the intervention. Assuming that 25% to 50% of patients with positive lymph nodes would benefit from a lymph node dissection, the procedure would affect only 5% to 10% of the entire study population and would require many more patients than were entered into the trials. The Mayo Clinic trial was faulted for having too few patients with intermediate-thickness (ie, >1.5 mm) melanoma and for technical issues related to insufficient lymph nodal mapping, which may have influenced the outcomes.91 The World Health Organization study was criticized for unequal ulcerated lesions and a low percentage of male patients (which result in a high risk for nodal involvement).92 Balch et al94 reported on a more recent randomized prospective trial to address the same issue in patients with intermediate-thickness melanoma (1-4 mm) and again found no survival advantage in patients undergoing ELND. Subset post hoc analysis revealed that patients with 1- to 2-mm-thick lesions who were older than 60 years had a survival benefit with ELND. These data were reanalyzed with longer follow-up and confirmed the earlier findings.12 Overall, no survival advantage was seen with ELND vs observation (77% vs 73%; P=.12). In subset analysis, patients with nonulcerated lesions (84% vs 77%; P=.03), melanomas with a thickness of 1.0 to 2.0 mm (86% vs 80%; P=.03), and limb melanomas (84% vs 78%; P=.05) had a better overall survival.12 SubseMayo Clin Proc.

•

quently, the World Health Organization Melanoma Program reported the results of another randomized trial that evaluated ELND in patients with truncal melanomas with a thickness of 1.5 to 4.0 mm, which once again demonstrated no advantage for ELND. No statistical difference was seen in overall 5-year survival rates between immediate (61.7%) and delayed (51.3%) lymph node dissection (P=.09); however, for patients who were found to be lymph node positive at the time of ELND compared with patients who developed clinically palpable lymph node metastases and underwent a therapeutic lymph node dissection, a 5-year survival benefit was seen (48.2% vs 26.6%; P=.04).93 In summary, randomized surgical trials fail to support a role for ELND in patients with clinically negative lymph nodes. SLN BIOPSY Even though ELND dissection has not been found to have a survival advantage, the patient’s lymph node status carries significant prognostic information and aids in decisions for adjuvant therapy and entry into clinical trials. This has been the impetus for the development of the SLN biopsy procedure. Sentinel lymph node biopsy is a technique used to identify and resect the first lymph node(s) to drain lymphatic flow from the primary tumor site. Sentinel lymph node biopsy allows for staging of the lymph node basin with minimal morbidity and facilitates selection of patients for additional complete lymph node dissection. The concept for using this procedure is that the status of the SLN is reflective of the status of the entire lymph node basin; therefore, therapeutic decisions can be made on the basis of the analysis of the SLN. The surgical principles of SLN biopsy were developed by Morton et al.95 The procedure as initially performed used a vital blue dye, 1% isosulfan blue, that was injected intradermally around the primary melanoma.95 After a brief period, a small incision was made over the primary draining lymphatic basin, and the “blue” node was excised and sent for pathologic analysis. Morton et al initially studied 223 patients with clinical stage I disease. The success in identifying the SLN was 89% in the groin, 81% in the neck, and 78% in the axilla. Nodal metastases were found in 41 (18.4%) of the 223 cases. The SLN accurately predicted the histologic findings of the lymph node basin in 40 (97.6%) of the 41 cases. Complications were minimal and included presence of dye in the urine for 24 hours, retention of blue dye at the injection site up to 2 months, wound edge necrosis (4.0%), seroma (5.5%), and infection (4.8%). The SLN biopsy technique was further refined by the addition of radioisotope technetium Tc 99m sulfur colloid96 to identify the sentinel node. The radionucleotide is injected intradermally around the primary melanoma at least 2 hours before surgery. Immediately before surgery, 1 mL

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

497

MALIGNANT MELANOMA IN THE 21ST CENTURY

TABLE 4. Sentinel Lymph Node Biopsy Series Series

Sample size

Localization successful (%)

Gershenwald et al33 Joseph et al99 Morton et al100 Morton et al101 Leong et al102 Mayo Clinic, Scottsdale, Ariz*

612 600 551 584 163

95 99 93 95 98

413

98

*B.A.P., unpublished data, 2006.

of 1% isosulfan blue is injected around the tumor. Intraoperatively, a handheld gamma probe is then used along with the vital dye to find the “hot” and/or “blue” node. The ability to find the SLN is increased to 96%. Preoperative lymphoscintigraphy is imperative to determine that the lymph node basin is at risk; patients with nonextremity melanomas may have drainage patterns different from classic anatomical teaching in up to 60% of cases, and more than 1 basin can be at risk 6% to 58% of the time.97,98 Not only can the main lymph node basin be identified but also in-transit lymph node drainage sites (popliteal, epitrochlear, scapular, or brachial) can be defined. Without this preoperative assessment of lymphatic drainage, potential metastatic disease could be missed. Other institutions, including our own, have used this combined technique with similar success (Table 4).33,99-102 An SLN is positive in approximately 20% of patients (primary tumors >1 mm thick), with the exact risk depending on the thickness of the primary lesion and presence of ulceration. Approximately 10% of all cases are upstaged by a more complete evaluation of the sentinel node with serial sectioning and immunohistochemical analysis (HMB-45 and S100). The average number of SLNs harvested from a lymph node basin ranges from 1.3 to 2.1. Drainage to more than 1 lymph node basin occurred in 15% to 27% of patients. Drainage to in-transit unusual lymph node basins occurred in less than 10% of cases. Head and neck melanomas have the highest localization failure rate. For patients with positive SLNs who have undergone a completion lymph node dissection, the likelihood of finding additional nodes involved is approximately 20%,103 with the risk depending on the thickness of the primary lesion, the size of the involved SLNs, and the number of positive SLNs. The local failure rate after an SLN procedure is low (1.8%4.8%). The results of SLN analysis are predictive of overall survival. Patients with negative SLNs had a 4-year survival rate of 85% compared with those with positive SLNs who had a 4-year survival rate of 45%. Previous wide local excision of the melanoma does not appear to negate the reliability of the SLN biopsy, provided that a flap rotation was not used to cover the defect.104 498

Mayo Clin Proc.

•

Controversy exists regarding the utility of performing an SLN procedure for thin melanomas (ie, ≤1 mm) and for thick melanomas (>4 mm). Thin melanomas account for approximately 70% of all newly diagnosed cutaneous melanomas. Although most patients with thin melanomas have an excellent long-term prognosis, a small proportion develops metastatic disease. Routinely performing SLN biopsy in these patients yields a positive result in approximately 5%. Attempts are under way to identify prognostic factors to better select these patients to avoid performing SLN procedures in the vast majority who have uninvolved SLNs. Several high risk factors for SLN positivity in these patients have been identified, including a high mitotic rate, tumor ulceration, male sex, and presence of a vertical growth phase, but none have been consistent among studies.53 In contrast, the prognosis of patients with thick melanomas is relatively poor, and the impact of lymph node positivity is unclear. Studies have demonstrated that up to 40% of patients in this group have a positive SLN. Patients with positive SLNs appear to have a worse prognosis, with higher rates of relapse105 and worse survival rates.106,107 On the basis of these data, SLN evaluation should be considered routine in this subset. Routine evaluation of SLNs is performed using conventional hematoxylin-eosin staining followed by immunohistochemical analysis. No routine immunostaining guidelines exist. Most institutions perform S100 immunostaining with the addition of MART-1 and/or HMB-45 if the hematoxylineosin staining result is negative. Recently, reverse transcriptase–polymerase chain reaction (RT-PCR) was used to evaluate SLN tissue and was shown to be more sensitive than immunohistochemical analysis alone. Positivity by RT-PCR was noted in approximately half of patients with pathologic analysis–negative SLNs. Among patients with pathologic analysis–negative SLNs, those with RT-PCR positivity were at a higher risk of disease recurrence and death.108 Subsequent studies have confirmed the value of RT-PCR in predicting a subset of patients with a higher risk of recurrence but do not confirm the value in predicting survival.109 However, RT-PCR is expensive and technically demanding. Moreover, RT-PCR has a high rate of false positivity (ie, most patients who have a negative SLN by immunohistochemical analysis and a positive SLN by RTPCR do not have disease recurrence). On the basis of these factors, as well as on early reports from the ongoing Sunbelt Melanoma Trial, which addresses the utility of RTPCR in evaluating lymph nodes, the use of RT-PCR should be considered experimental. Despite its obvious advantage, the technique of SLN biopsy for melanoma staging has not been widely accepted. Recent analysis of Surveillance, Epidemiology, and End Results data demonstrates that only approximately 50% of

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

MALIGNANT MELANOMA IN THE 21ST CENTURY

patients with melanoma who are eligible for SLN biopsy undergo the procedure.110 Most of the controversy relates to the lack of any data demonstrating a survival advantage with SLN biopsy until recently. The interim results of the Multicenter Selective Lymphadenectomy Trial 1 were reported at the American Society of Clinical Oncology annual meeting in 2005.111 This trial randomized 1204 patients with larger than 1-mm lesions who underwent wide local excision to immediate SLN biopsy or observation. Patients with positive SLNs underwent a completion lymphadenectomy. No significant overall survival (primary goal) difference was found in patients who underwent the SLN procedure up front compared with those randomized to initial observation. However, several of the secondary aims of the study were positive. Patients randomized to the SLN biopsy arm up front had a better disease-free survival rate compared with those in the observation arm. Moreover, patients who had a positive SLN and underwent an immediate complete lymph node dissection had better survival rates than those in the observation arm who developed lymph nodal involvement subsequently (5-year survival rate, 71% vs 55%; P=.007).111 Thus, it would appear that routine use of SLN biopsy, followed by complete lymph node dissection if positive, has a prognostic and possibly some therapeutic value, especially in lymph node–positive patients. In light of these data, most melanoma surgeons advocate the use of SLN biopsy to stage their patients’ disease. SURGERY FOR RECURRENT AND STAGE IV DISEASE When possible, surgical excision for local recurrences and in-transit metastases is the most effective therapy. The same is true for regional metastases or recurrences in which complete lymph node dissection is the treatment of choice. Surgical resection can also be valuable in patients with metastatic disease, with reports of long-term survival. Current trials are under way to assess the impact of additional systemic therapy after surgical resection for selected patients with stage IV disease. The John Wayne Cancer Institute reported on the long-term survival of 1574 patients with melanoma who underwent surgical resection for stage IV disease.112 The number and location of metastases were the most powerful factors predicting overall survival. Median survival for those who underwent resection for metastases to skin or distant lymph nodes (35.1 months), lung (28.1 months), and gastrointestinal tract (36.7 months) was much better than for those who underwent resection for metastases to the adrenal gland (27.4 months), brain (21.9 months), and liver (18.2 months). Other studies have reported similar results, with those undergoing resection of lung and subcutaneous metastases or distant lymph nodes having the best long-term survival.113 Mayo Clin Proc.

•

ADJUVANT THERAPY Surgical resection of regionally metastatic stage III melanoma is only partially effective in ensuring long-term disease-free survival. Approximately 60% of these patients ultimately die of metastatic disease. Therefore, additional therapy that eradicates clinically undetectable micrometastases present at the time of primary surgical resection is desirable. INTERFERON ALFA The risk of recurrence of melanoma is substantial in deeply invasive primary melanoma and when lymph nodes are involved at diagnosis. The only adjuvant therapy for highrisk melanoma currently approved by the Food and Drug Administration (FDA) is interferon alfa 2b given at a high dose (20 million U/m2 for 5 days) for 1 month, followed by a lower dose (10 million U/m2 3 times weekly) for 11 months. Interferon was approved in 1995 on the basis of a pivotal trial (E1684) conducted by the Eastern Cooperative Oncology Group (ECOG). In that trial, 287 patients with either pathologic stage T4 (>4 mm depth) or lymph node positive disease (N1) were randomized to either interferon alfa 2b therapy or observation. At the time of the report, the treatment arm demonstrated improvement in time to progression by an average of 8 months, with a 1-year overall survival benefit (P=.0237).114 The benefit to the treated patients was associated with significant toxic effects, with dose reductions required in most patients. Subsequent confirmatory studies failed to reproduce the survival benefits noted in the E1684 trial. The North Central Cancer Treatment Group reported a study of 262 patients with earlierstage disease (stage I and II) who did not receive significant benefit from adjuvant high-dose interferon alfa therapy, although a trend toward prolonged survival was reported (6.6 vs 5.0 years; P=.4).115 The Intergroup study E1690, using the same eligibility criteria as E1684, initially showed a decreased risk of progression at 5 years of nearly 10% (P=.05)116 but no overall survival benefit or trend. Potential explanations for this difference include more patients with node-negative disease in E1690, higher rates of salvage therapy with interferon alfa in the observation group after progression, and improvements in surgical techniques compared with patients in E1684.117 A pooled analysis of 1916 patients and 716 observational controls from all ECOG trials using high-dose interferon alfa for melanoma (E1684, E1690, E1694, E2696) in the adjuvant setting was reported in 2004.118 The final analysis showed a significant increase in relapse-free survival (P=.006) but not overall survival (P=.42), controlling for poor prognostic factors such as relapse of disease at the time of treatment, ulceration, and enrollment in protocol

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

499

MALIGNANT MELANOMA IN THE 21ST CENTURY

E1684. Despite the positive impact on survival reported by E1694 (high-dose adjuvant interferon therapy vs G2-KLH/ QS-21 vaccine), the results of the pooled data have heightened the reluctance of many practitioners and patients to use adjuvant therapy with interferon in light of the substantial toxicity.119 However, a recent report suggested that the subset of patients who developed serologic or clinical evidence of autoimmunity after interferon therapy appeared to achieve survival benefit from treatment.120 These data suggest that improved patient selection may be critical in attaining improved overall survival outcomes with adjuvant interferon therapy. Efforts to identify these patient characteristics are currently under way. Concerns about toxicity associated with high-dose adjuvant interferon alfa therapy have prompted several investigators to evaluate lower-dose therapy for the same clinical settings. Lower-dose adjuvant interferon therapy has demonstrated less toxicity with possible trends toward delay of progression (less effective than high-dose therapy) and no effect on overall survival in node-positive and high-risk node-negative patients.116,121-127 However, prolonged treatments (>1 year) may lengthen time to recurrence, with progression-free survival and overall survival curves approaching results of untreated controls after cessation of therapy.121,126 GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR In an effort to boost tumor lysis through activation of cytotoxic macrophages, granulocyte-macrophage colonystimulating factor (GM-CSF) has been used in the adjuvant setting to treat high-risk melanoma. Spitler et al128 treated 48 patients with resected stage III or IV melanoma with a subcutaneous daily dose of 125 mg/m2 for 2 weeks on, 2 weeks off for at least 1 year. The improvement in progression-free survival over historical controls was substantial (37 vs 12 months; P<.001). This promising result has led to adjuvant GM-CSF being included in a phase 3 ECOG trial (E4697) to prospectively test its efficacy vs placebo. We eagerly await the results of this trial. Adjuvant GM-CSF therapy is gaining acceptance in clinical practice for patients at high risk of recurrence who do not wish to undergo adjuvant high-dose interferon alfa therapy or do not qualify for other adjuvant clinical trials. Despite the promising phase 2 data, caution must be used with historical control comparisons. CANCER VACCINES Both autologous and synthetic vaccine approaches have been used in patients with high-risk melanoma. Many of these vaccines appeared to have clinical activity when results are compared with historical controls129,130 or in patients with immune responses compared with nonrespond500

Mayo Clin Proc.

•

ers.129,131,132 Primary avenues of research have focused on the identification of novel melanoma specific/associated antigens (eg, MART-1, gp100, tyrosinase-related protein 1, gangliosides),117 optimization of the use of immune stimulants as vaccine adjuvants (eg, GM-CSF, incomplete Freund adjuvant, interleukin [IL] 2), and development of target-specific measures of efficacy. Vaccines, although unsuccessful to date in the metastatic setting, remain a robust area of research in the adjuvant setting. SYSTEMIC THERAPY FOR METASTATIC MELANOMA The prognosis of a patient with stage IV metastatic malignant melanoma in the 21st century remains poor. Despite decades of research efforts, the median survival time of a patient with disseminated melanoma is less than 9 months with a less than 5% probability of survival beyond 5 years of diagnosis.3,28,34,133 To date, the FDA has approved only 2 agents (dacarbazine and IL-2) for the treatment of stage IV melanoma. Although both agents have demonstrated modest tumor response rates, neither has resulted in a clinically meaningful prolongation of overall survival. Dacarbazine (5-3,3-dimethyltriazeno-imidazole-4-carboxamide), the first drug approved for the treatment of stage IV melanoma, is a parenterally administered DNAbinding agent that undergoes extensive metabolism in the liver and is eliminated primarily by the kidneys. In the liver, dacarbazine is metabolized by the cytochrome P450 isoenzyme system to its active metabolite 5-(3-methyl-1triazeno)-imidazole-4-carboxamide, which spontaneously decomposes to the major metabolite 5-aminoimidazole-4carboxamide. Approximately half a dose is excreted unchanged in the urine by tubular secretion. Initially reported as a potentially active agent in disseminated melanoma,134 dacarbazine was attributed with an overall response rate of 22%, with the greatest activity in patients with low tumor burden and nonvisceral metastases.135 There was no impact on survival. These early clinical results have been reproduced in several subsequent studies and have been the foundation of a variety of chemotherapeutic and immunotherapeutic combination studies using dacarbazine as the primary active agent. In the most recent phase 3 clinical trial comparing dacarbazine with its oral analogue temozolomide for first-line therapy for patients with stage IV melanoma, the response rate for the dacarbazine treatment arm was 12.1%.136 The response rate with temozolomide was comparable at 13.5%. Since the publication of these data, most practicing oncologists have elected to use oral temozolomide vs intravenous dacarbazine because of, among other reasons, ease of administration. Orally active temozolomide, once absorbed (100% bioavailability), is nonenzymatically degraded in normal pH to the same active compound as dacarbazine (5-[3-methyl-1-triazeno]-

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

MALIGNANT MELANOMA IN THE 21ST CENTURY

imidazole-4-carboxamide). Elimination is primarily via the kidneys, requiring dose adjustments in patients with severe renal insufficiency. The most common toxic effects of temozolomide therapy are marrow suppression (thrombocytopenia) and constipation. Currently, temozolomide is approved by the FDA for treating anaplastic astrocytoma and glioblastoma multiforme. Approval for treatment of metastatic melanoma is pending. The second agent approved by the FDA for the treatment of stage IV melanoma is IL-2, a recombinant hormone of the immune system originally described as a Tcell–derived growth factor and initially clinically used in the context of lymphokine activated killer cell therapy.137-143 Interleukin 2 received initial FDA approval for use in renal cell carcinoma in 1992, having demonstrated durable responses in select patients.144 By 1999, similar results were obtained in several studies of advanced-stage melanoma.145-148 A pooled analysis of 270 patients treated with high-dose bolus IL-2 (600,000-720,000 IU/kg administered every 8 hours for up to 14 consecutive doses for 5 days) resulted in overall objective response rates of 16% (6% complete responses).145 Best clinical responses were observed in patients with metastatic disease that involved soft tissues and lymph nodes. The overall median survival time was 11.4 months. Treatment was associated with significant toxic effects, with some patients requiring intensive care support. The more common (>30%) severe adverse effects (grade 3 and 4) were hypotension (45%), vomiting (37%), diarrhea (32%), and oliguria (39%). Because of the significant treatment-associated toxic effects, this form of therapy is currently used primarily in medical centers with appropriately trained specialized staff. Encouraged by the results of the high-dose IL-2 data, efforts proceeded in attempting to combine this treatment with other agents that had demonstrated clinical activity in melanoma (dacarbazine, interferon alfa, and cisplatin). The most important of these endeavors was the use of combination biologic (IL-2 and interferon alfa) and chemotherapeutic (cisplatin, vinblastine, and dacarbazine [CVD]) treatments referred to as biochemotherapy.149-153 Originally pioneered by Legha et al,150,152-154 this approach was based on the combination of the conventional CVD chemotherapeutic regimen (cisplatin, 20 mg/m2 daily for 4 days; vinblastine, 1.6 mg/m2 daily for 4 days; and dacarbazine, 800 mg/m2 once) followed by biotherapy with high doses of IL2 (9 × 109 IU/m2 intravenous infusion for 4 days) and interferon alfa (5 × 106 IU/m2 subcutaneously for 5 days). Initial reports demonstrated remarkable objective responses in the range of 69%.152 Despite the significant improvement in objective responses and the associated severe adverse effects (15% of the treated patients required intensive care support), the median overall survival was Mayo Clin Proc.

•

only 13 months (among 62 treated patients). This effort led to a phase 3 randomized clinical trial in which 190 patients with advanced melanoma were randomized to either chemotherapy (CVD) or biochemotherapy (CVD, IL-2, and interferon); greater clinical efficacy was shown in the biochemotherapy arm (overall response rates of 25% vs 48%).155 Despite significant toxic effects, the median survival time of the biochemotherapy arm was minimally improved (11.9 and 9.2 months). The addition of biotherapy appeared to improve the response rates but had no meaningful impact on overall survival. The final analysis of the benefits of biochemotherapy for the treatment of stage IV melanoma came with Intergroup study E3695, in which CVD was again compared with CVD, IL-2, and interferon.156 Preliminary analysis of this study demonstrated no overall survival advantage of the CVD, IL-2, and interferon arm. Once again, systemic therapy had failed to change the natural history of metastatic melanoma. Currently, there are no standard systemic therapeutic regimens that offer significant prolongation of survival for patients with metastatic melanoma. Participation in clinical studies should be considered when possible for patients with advanced melanoma. NOVEL THERAPEUTICS It has become increasingly clear that clinically effective therapy for metastatic malignant melanoma will likely involve a combination of cytotoxic drugs with biologic agents directed at inhibiting tumor vasculature (antiangiogenesis agents) and stimulating antitumor immunity. A multimodal approach is likely to address the deficiencies of individual treatment strategies. A large body of work already exists that describes individual efforts in all these treatment approaches with emerging combination therapeutics. Therapeutic Cancer Vaccines. Therapeutic cancer vaccines represent one of the most heavily investigated and highly anticipated therapeutic strategies in the field of melanoma therapeutics. The basic premise of these interventions is the generation of increased numbers of vaccineand tumor-specific cytotoxic T lymphocytes using vaccines administered to patients with metastatic melanoma, with the hope of inducing tumor regression or preventing tumor relapse in patients with resected melanoma who have a high risk of recurrence. The types of vaccines and routes of administration have ranged from autologous and allogeneic tumor cell lysates, engineered malignant melanocytes, melanoma tumor-specific peptides, autologous tumor-derived heat shock proteins, intratumoral injection of immune adjuvants, and autologous dendritic cell vaccines. These vaccines have been used either alone or in combination with immune modulators thought to potentiate their efficacy. Most notable (and most studied) of the

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

501

MALIGNANT MELANOMA IN THE 21ST CENTURY

therapeutic melanoma vaccines is the polyvalent allogeneic irradiated whole-cell vaccine (PACV), developed from 3 allogeneic melanoma cell lines by Dr Donald L. Morton, and Melacine, a preparation of lyophilized lysates of 2 allogeneic melanoma cell lines combined with a novel immune adjuvant (Detox-PC) developed by Dr Malcolm S. Mitchell. Both vaccines were developed on the premise of multiple antigen targeting directed against both known and unknown melanoma antigens derived from cultured, allogeneic human melanoma cell lines. The experience with PACV demonstrated that patients with resected stage IV melanoma adjuvantly treated with PACV had improved 5year survival rates compared with historical controls (39% vs 19%).157 Interestingly, a subset analysis of 77 patients showed that those exhibiting evidence of immunization (IgM antibodies to TA90 and positive vaccine-specific delayed-type hypersensitivity) had superior survival compared with immunized patients with no evidence of effective immune response (75% vs 8%), implying a specific therapeutic effect of the vaccine.131 These nonrandomized data suggested a benefit for adjuvant therapy using the PACV vaccine and gave rise to prospective randomized clinical studies in high- and low-risk patients with melanoma who had undergone resection. Unfortunately, in April 2005, the phase 3 placebo-controlled clinical trial evaluating the clinical benefit of adjuvant PACV therapy in high-risk patients with melanoma was closed before completion of accrual because of lack of clinical benefit. The results of the parallel study in “low risk of relapse” patients have not yet been reported. Published experience with the Melacine preparation was similar to that of PACV. Initial phase 1 and phase 2 clinical data in patients with stage IV melanoma suggested effective immunization in 50% and objective responses in almost 20% of treated patients.158,159 Unfortunately, a large placebo-controlled phase 3 clinical trial of patients with T3 N0 M0 disease conducted by the Southwest Oncology Group failed to demonstrate a clinical benefit in the treatment arm.160 Interestingly, subset analysis showed a disease-free survival benefit in patients expressing HLA-A2 and C3 haplotypes.161 Whether these data are sufficient to support further clinical studies with Melacine is currently under discussion.162 Even though an effective vaccine for melanoma has not yet been developed, the recent FDA approval of a human papillomavirus vaccine for the prevention of cervical cancer provides encouragement for further research in cancer vaccines. Angiogenesis Inhibitors. The recent FDA approval of bevacizumab (anti–vascular endothelial growth factor A) and sunitinib maleate for colon and renal cell carcinoma, respectively, has firmly established the place of angiogen502

Mayo Clin Proc.

•

esis inhibitors in cancer therapy.163,164 Similar angiogenesis-targeting agents have also been tested in patients with stage IV melanoma. The most notable of this class of agents to be tested in advanced-stage melanoma is thalidomide. Used alone or in combination with temozolomide, thalidomide has been unsuccessful in significantly improving the outcomes of patients with metastatic melanoma.165-171 Similar angiogenesis inhibitors (sunitinib malate, carboxyamido-triazole, TNP-470, SU5416, CC-5013, SU5416, BAY 12-9566, squalamine, or CCI-779) used in singleagent phase 1 (and 2) clinical trials have failed to significantly affect the natural history of metastatic melanoma.172-179 Agents currently undergoing phase 2 testing either as single antiangiogenesis agents or in combination with chemotherapy for stage IV melanoma include RAD001 (rapamycin analogue), sunitinib maleate in combination with temozolomide or paclitaxel, and carboplatin in combination with bevacizumab. Early reports on clinical outcomes in these studies are expected by middle to late 2007. To date, the experience with antiangiogenesis agents in the treatment of stage IV melanoma seems to suggest that combinations of these agents with chemotherapeutic drugs may be of potentially greater utility vs single-agent therapy. Novel Cytotoxic Agents. One of the more unexpected developments in recent years is the reported efficacy of the combination of paclitaxel and carboplatin in the treatment of metastatic melanoma. Although originally tested in 2 small phase 2 clinical trials and deemed not sufficiently clinically active, recent evidence suggests that the combination of paclitaxel and carboplatin may be worth further consideration.180-182 This combination has become particularly interesting after early reports of encouraging clinical results emanating from a study in which the addition of sorafenib (BAY 43-9006)183-185 to paclitaxel and carboplatin resulted in objective response rates in excess of 50%.183 Sorafenib is a small molecule, multityrosine kinase inhibitor that, among other mechanisms of action, appears to be cytotoxic in malignant cells bearing b-raf mutations, as has been described in melanoma.186-188 The combination of paclitaxel, carboplatin, and sorafenib is currently undergoing phase 3 testing by the US cancer cooperative groups (E2603). The renewed interest in taxanes for the treatment of melanoma has resulted in a number of novel taxanes (ie, ABI-007) being tested in several ongoing phase 2 clinical trials. Last and certainly not least, another noteworthy agent currently undergoing phase 3 clinical testing in resected and advanced melanoma is anti-cytotoxic T-lymphocyte– associated protein 4 (CTLA4).189 Anti-CTLA4 is a humanized antibody directed at a down-regulatory receptor on activated T cells. The proposed mechanism of action is inhibition of T-cell inactivation, allowing expansion of naturally developed (or vaccine stimulated) melanoma-

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

MALIGNANT MELANOMA IN THE 21ST CENTURY

specific cytotoxic T cells. Original reports of the use of anti-CTLA4 in patients with metastatic melanoma describe remarkable efficacy in a small group of patients.190 This agent is currently in phase 3 clinical testing in patients with metastatic melanoma, and planning is under way for phase 3 trials in patients with resected tumors at high risk of disease relapse. We eagerly await the results of these studies. RADIATION THERAPY Melanoma is widely believed to be a radioresistant tumor; historically, this has limited the enthusiasm of physicians to use radiation therapy to treat this disease. The concept of radioresistance of melanoma has been interpreted to mean that radiation therapy is not useful for the treatment of melanoma, a perception that is incorrect. Radiation therapy has been successfully used for primary treatment of ocular melanoma and lentigo maligna melanoma. Melanoma is the most common primary tumor of the eye and was traditionally treated with enucleation. Early reports revealed promising outcomes for patients treated with eye plaques that contained radioisotopes (brachytherapy). These plaques are sewn to the outside of the globe adjacent to the tumor to ensure proximity between the tumor and the radioactive sources. The Collaborative Ocular Melanoma Study was performed to compare enucleation to brachytherapy with the radioisotope iodine 125.191,192 Included were melanomas 2.5 to 10 mm in apical height and no more than 16 mm in longest basal diameter. After staging, 1317 patients were randomly assigned to either enucleation or radiation therapy. The dose prescribed to the tumor apex was 85 Gy. The 5-year survival rates were 81% for enucleation and 82% for radiation therapy (P=.48). The primary advantage of radiation therapy was preservation of useful vision, which occurs in approximately half of the patients who have undergone irradiation. Lentigo maligna melanoma generally occurs in elderly patients in sun-exposed regions of the body. Surgical resection is generally considered the treatment of choice. However, radiation therapy has been used in selected patients who were not optimal candidates for resection.193-195 Harwood and Lawson,193 from the Princess Margaret Hospital, treated 28 patients with lentigo maligna melanoma using radiation therapy, and local failure occurred in 2 patients (7%). They also gave radiation therapy to 23 patients for lentigo maligna, and 2 patients (9%) experienced local disease recurrence. Tsang et al194 updated the Princess Margaret Hospital experience with patients with lentigo maligna who underwent resection (18 patients) or radiation therapy (36 patients). The 3-year local control rates were 94% for resection and 90% for radiation therapy. They concluded that radiation therapy was an excellent alternaMayo Clin Proc.

•

tive to surgical excision with low morbidity and acceptable long-term cosmesis. Similar results with radiation therapy have been reported at other institutions.195 Radiation therapy has been used for the primary treatment of nodular melanomas. Johanson et al196 described 9 patients treated with radiation therapy for gross residual disease after partial resection. Seven (78%) of the 9 patients achieved local control. Additionally, 9 (39%) of 23 patients with recurrence after resection achieved a complete response with salvage radiation therapy. Radiation therapy has been used as an adjuvant therapy after resection. Creagan et al197 reported the results of a phase 3 trial performed at the Mayo Clinic in Rochester, Minn, which compared adjuvant radiation therapy with observation after lymph node dissection in 56 patients with involved regional lymph nodes. The radiation therapy was delivered at a dose of 50 Gy in 28 fractions administered in a split-course fashion with a 3- to 4-week break in the middle of treatment. The median duration of freedom from recurrence was 20 months with adjuvant radiation therapy vs 9 months without radiation therapy (P=.08). The median survival was 33 months with adjuvant radiation therapy vs 22 months without radiation therapy (P=.09). The reported interpretation of this study has been criticized on 3 key points: (1) insufficiently large cohort to detect subtle differences in survival; (2) poorly designed radiation therapy program, which included a break that decreased the treatment efficacy; and (3) no stratification for other significant prognostic variables. However, despite these weaknesses, the findings were provocative and should motivate further investigation. Ang et al and Ballo et al reported the experiences of the M. D. Anderson Cancer Center investigators198-208 who administered postoperative radiation therapy for high-risk patients with melanoma.209 They recommended the following indications for postoperative radiation therapy to the primary site: desmoplastic melanoma, positive margins, locally recurrent disease, and tumors larger than 4 mm in thickness with either ulceration or satellitosis. Additionally, they recommended postoperative nodal irradiation for the following indications: extracapsular extension, 4 or more lymph nodes, lymph nodes 3 cm or larger in diameter, recurrent nodal disease, SLN involvment, and complete lymph node dissection not planned. They have used these indications and a program of 30 Gy in 6-Gy fractions, each given twice weekly using primarily electron radiation therapy. This program has been used at many sites and has achieved generally high rates of local-regional control (89% overall).175 This level of local-regional control was much higher than that of their historical group and that reported in the literature (50%) of high-risk patients undergoing resection alone. Although disease control after resection plus radiation therapy was not site dependent, compli-

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

503

MALIGNANT MELANOMA IN THE 21ST CENTURY

cations appeared related to treatment location. For patients with epitrochlear, cervical, axillary, or groin lymph node disease, the corresponding 5-year rates of symptomatic lymphedema were 0%, 1%, 20%, and 27%, respectively (P<.0001).175 These differences in risk of treatment complications based on location have led Ballo et al to use more stringent criteria that require 2 or more indications for postoperative adjuvant radiation therapy for groin disease and less stringent criteria (>2 lymph nodes or >2 cm in diameter) for cervical disease. More commonly, radiation therapy has been used for palliation of symptomatic sites of melanoma metastases. One area of great interest is determining the optimal dose-fractionation scheme for use in this setting. Two phase 3 trials have compared various fractionation patterns.210,211 Overgaard et al210 reported on 35 tumors in 14 patients with metastatic or recurrent melanoma who were randomized to receive either 9 Gy 3 times or 5 Gy 8 times, delivered twice weekly. Complete and persistent regression was found in 24 (69%) of 35 tumors and partial response in 10 (29%) of the 35 tumors. The overall response rate was 97%. No difference was observed between the 2 treatment regimens. Sause et al211 reported the results of Radiation Therapy Oncology Group trial 83-05, which randomized patients with measurable lesions to either 8.0 Gy 4 times once weekly (62 patients) or 2.5 Gy 20 times 5 days a week (64 patients). Patients in the 8.0-Gy arm exhibited a complete remission of 24.2% and a partial remission of 35.5%. Those in the 2.5-Gy arm exhibited a complete remission of 23.4% and a partial remission of 34.4%. No difference was found between arms. Although there was much radiobiological-based speculation that melanoma would respond better to programs with fewer larger doses of radiation therapy, this was not the case for metastatic melanoma. Brain metastases pose special challenges because of the poor associated prognosis. Traditional therapy was wholebrain radiation therapy, which generally resulted in effective palliation and a median survival between 3 and 4 months. Recent studies have suggested that more aggressive management can positively influence survival. Meier et al212 reported on 100 patients who received treatment for brain metastases from melanoma. Their multivariate analysis confirmed that external beam radiation therapy, surgery, stereotactic radiosurgery, chemotherapy, and the location of brain metastases were independent and significant prognostic factors of survival. Thus, although melanoma is a relatively radioresistant tumor, it is certainly not radioincurable. The utility of radiation therapy depends on the therapeutic index one can achieve using well-reasoned indications and optimal techniques of irradiation. Radiation therapy has been used successfully for primary therapy, adjuvant therapy, and palliation of metastatic melanoma. Further investigation of the use 504

Mayo Clin Proc.

•

of radiation therapy for melanoma should not be hindered by the notion of radioresistance. RARE MELANOMAS MELANOMA OF THE EYE Uveal melanomas are rare cancers. The incidence of these cancers is approximately 5 to 7 new cases per 1 million persons per year.213 They occur much more commonly in whites than in African Americans.214 There are no known risk factors other than a family history or ocular melanocytosis.215 Ocular melanocytosis causes hyperplasia of deep scleral melanocytes, producing a grayish discoloration of the sclera. Besides uveal melanomas, ocular melanocytosis can cause iris heterochromia, choroidal heterochromia, and glaucoma. The 3 types of uveal melanomas are iris, ciliary, and choroidal. The ciliary and choroidal melanomas are similar, whereas the iris melanoma appears to be different in pathologic findings and metastatic potential. Iris melanomas account for only 3% to 5% of all uveal melanomas. CILIOCHOROIDAL MELANOMAS In the eye, the ciliochoroidal melanomas expand and cause visual loss and ultimately pain (Figure 1, A and B). Systemically, they can metastasize. Typical areas of metastasis are the liver, lung, and rarely other organs.216 The diagnosis of ciliochoroidal melanomas depends on certain clinical and echographic findings, and studies have shown that the diagnostic accuracy of these currently available techniques is a 99% ability to make a proper diagnosis. There can be dilation of vessels on the sclera in the area of the tumor, which are called sentinel vessels. The fundus findings show the presence of a pigmented or mildly pigmented choroidal mass that is dome shaped or mushroom shaped. The mushroom shape occurs if the overlying Bruch membrane, which acts like a barrier to growth, is ruptured in a focal area. There can be an overlying exudative retinal detachment. Orange pigment can also be present on the surface of the tumor. This is caused by lipofuscin pigment collecting in the overlying, poorly functioning retinal pigment epithelium. Fluorescein angiography can show intrinsic vascularity of the tumor and punctuate areas of leakage at the level of the retinal pigment epithelium. This leakage is from breakdown of the usual tight junction between the retinal pigment epithelium cells. Ultrasonography typically shows medium to low internal reflectivity of the lesion with a decrescendo pattern of the internal reflectivity and choroidal excavation. These ultrasound findings are distinctly different from other differential possibilities, including choroidal metastases, macular degeneration, choroidal hemangiomas, and choroidal osteomas. These typically show high internal reflectivity by ultrasonography.

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

MALIGNANT MELANOMA IN THE 21ST CENTURY

FIGURE 1. Melanomas of the eye. A and B, Photographs of a ciliochoroidal melanoma in a pseudophakic eye. C, Histologic photomicrograph showing mixed epithelioid and spindle cells in melanoma shown in section A. D, Positron emission tomography and computed tomography showing liver metastases. E, Iodine 125 plaque brachytherapy device being placed on the sclera. F, Iris melanoma with prominent vessels. G, Same iris melanoma as in section F now has blood on its surface. H, Iris of the same patient as in section F after iridocyclectomy of the iris melanoma.

Evaluation for metastasis should be made at the time of diagnosis. The most common site for metastasis is the liver, followed by the lung and much less commonly other organs. Evaluation should include liver function tests, including γ-glutamyl-transferase. Either PET/CT or a chest x-ray examination combined with liver ultrasonography should be performed (Figure 1, C). Risk factors for metastasis have traditionally been size of the tumor, location of the tumor, and the histopathologic type.214,216,217 Tumors with a base less than 16 mm and a height less than 8 mm had a 20% rate of metastasis at 10 years.218 Tumors with a base less than 16 mm and a height greater than 8 mm had a 35% rate of metastasis at 10 years. Tumors with a base greater than 16 mm have a 60% rate of metastasis at 10 years. Spindle cell tumors have a better prognosis than a mixed cell type, whereas an epithelioid cell type has the worst prognosis214,216,217 (Figure 1, D). With molecular techniques, new risk factors are being discovered. At the genetic level, fluorescence in situ hybridization analysis has shown that another more recently noted Mayo Clin Proc.

•

risk factor for metastasis is monosomy 3.219 In addition, at the molecular level, inhibitor of DNA binding 2 (Online Mendelian Inheritance in Man No. 600386) suppression then may cause up-regulation of E-cadherin and downregulation of DNA binding 2, and up-regulation of Ecadherin appears to be related to metastatic potential of the tumor.220 How this is related to metastasis is still unknown. More recent studies have shown that periodic acid–Schiff– positive loops are a separate independent risk factor for the development of metastasis.221 These loops have been shown to be vascular loops that consist of a combination of endothelial cells and tumor cells. The more of these present, the worse the prognosis.222,223 Unfortunately, aside from the size, all the other prognosticators are found at the time of enucleation of the eye. In many patients, the eyes are not removed because studies have shown that, for tumors with a base of less than 16 mm and a height of 10 mm or less, plaque brachytherapy treatment results in the same prognosis as enucleation of the eye.217 Vision is ultimately lost because of radiation retinopathy and radiation optic

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

505

MALIGNANT MELANOMA IN THE 21ST CENTURY

neuropathy, but the eye is retained. This allows patients to have the option of retaining their eye and peripheral vision for approximately 2 to 3 years, but there is some concern with retaining the eye since the success rate of brachytherapy in preventing further growth of the tumor is 88% to 90% (Figure 1, E). The treatment of small choroidal melanomas with a tumor height lower than 3 mm is still in question. Many of these grow slowly, and becuase treatment can cause visual loss, treatment should be considered if certain prognostic indicators of further growth are present, namely, documented evidence of growth, orange pigment on the surface, overlying subretinal fluid, proximity to the optic nerve or macula, and a height of at least 2 mm. Previously, the use of transpupillary thermotherapy alone had been considered reasonable treatment for small melanomas, but recent data raise questions about whether these patients develop difficult-to-detect posterior extensions of residual melanoma.224 Because vascularity may be an important and independent indicator for prognosis, methods to determine vascularity short of removal of the eye are needed. Mueller et al225 attempted to look at the vascularity by using indocyanine green. This approach looks only at the superficial part of the tumor and only qualitatively determines whether there are vessels on the surface of the tumor. The indocyanine green method cannot evaluate or quantify the presence of vessels located deep within the tumor, which may represent the bulk of the tumor vascularity. Buerk et al226 attempted to do this with magnetic resonance imaging by determining the relative enhancement over time. To date, this has been the best attempt to put some quantitation to the vascularity of a choroidal melanoma. The problem with this technique is that it is only a relative enhancement, and so a relative uptake over time is the best that can be accomplished with this technique. Once metastasis occurs, the prognosis for the patient is poor. The death rate is 80% at 1 year and 92% at 2 years.218 There is no known treatment that is effective for metastatic choroidal melanoma, although multiple therapies are being tried. Because the uveal melanomas express vascular endothelial growth factor, which helps the tumor attract vessels to help nourish the tumor, attempts at the use of vascular endothelial growth factor inhibitors are being considered as well.227 Patients who have had choroidal melanomas should undergo liver function tests, including γ-glutamyltransferase performed every 6 months. Chest x-ray examination or PET/ CT should probably be performed on a yearly or every 1.5year basis. IRIS MELANOMAS Iris melanomas tend to have a better prognosis and a low potential for metastasis.228-230 Many are actually catego506

Mayo Clin Proc.

•

rized as spindle cell nevi or epithelioid cell nevi. Iris tumors tend to grow more frequently locally, and metastasis occurs in no more than 3% to 10% of cases at 10 years (Figure 1, F-H). Important risk factors for metastasis are development of intractable glaucoma, documented rapid growth, and prominent vessels. Complications from local growth include recurrent hemorrhages. Sometimes, for locally growing iris melanomas that are causing complications, for instance, anterior chamber hemorrhages, the iris lesion can be removed. Occasionally, the lesion can be radiated with plaque brachytherapy. For patients who have developed glaucoma refractory to antiglaucoma medications, enucleation can be considered. MUCOSAL MELANOMA Uncommonly, melanomas arise in sun-sheltered internal sites, usually in the mucosa of the head and neck, gastrointestinal tract, urinary tract, and vagina. One epidemiological study determined that 1.3% of all melanomas arose in such mucosal locations.231 Because of their rarity, the pathophysiology, etiology, risk factors, epidemiology, and clinical behavior of these tumors have not been well characterized. Mucosal melanomas arise from resident melanocytes that are normally present in the mucosa. Benign melanocytic lesions occur in some of these sites (eg, nevi can be found in oral mucosa) and may represent precursor lesions.232 The genetic pathway followed by mucosal melanomas is somewhat distinct from that of UV radiation–induced dermal melanomas. For example, the genetic abnormalities typical of dermal melanomas (eg, BRAF and N-Ras mutations) are rarely found in mucosal melanomas.233-236 Biological differences between mucosal and dermal melanoma result in several differences in clinical behavior. For example, compared with their dermal counterparts, mucosal melanomas (1) are not etiologically linked to UV exposure (correspondingly the population incidence has remained stable), (2) develop in older patients, (3) have a much worse prognosis, and (4) are disproportionately more common in populations other than white people.231,237,238 The most common sites of involvement of mucosal melanomas are the head and neck region (oropharynx, 55%), followed by the anus (24%), genitalia (vagina, 18%), and the urinary tract (3%). The mean age at diagnosis is 67 years, with a female preponderance (mainly because the male genital counterpart to vaginal melanomas is exceedingly rare).231,239 Clinically, these tumors manifest with local symptoms (eg, bleeding, ulceration, mass effect) or with signs of metastatic disease. Because these tumors are found in inaccessible locations and the index of clinical suspicion for melanoma at these sites is low, internal melanomas are often diagnosed later in the disease course. When a mucosal melanoma is detected, an obvious initial

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

MALIGNANT MELANOMA IN THE 21ST CENTURY

diagnostic approach is to rule out a mucosal metastasis from a dermal primary lesion.240 However, some pathological features have been recognized that are typical for primary mucosal lesions; therefore, the diagnosis of a mucosal primary tumor is not always a diagnosis of exclusion.241 Overall, the prognosis of patients with mucosal melanoma is relatively poor, with an overall 5-year survival rate of only 25% (compared with 80% for all skin melanomas). The prognosis of those with anal and rectal melanomas is even worse, with a 5-year survival rate of only 20%. Clinically, mucosal melanomas are more aggressive and deeper than dermal melanomas; it is unclear whether this finding is the result of a delay in diagnosis (ie, the inverse of a lead-time bias) or represents an underlying biological difference. The most important prognostic features are depth and lymph nodal involvement. Mucosal lesions have a higher propensity to metastasize than dermal lesions of similar thickness; presumably, the lack of mucosal fat allows for early lymphatic spread. Lymph nodal involvement is common in mucosal melanomas (40%) and is even more common in anal melanomas (60%).231 Lymph nodal involvement portends a poor prognosis. Because of the rarity of these tumors, no clinical trials are available on which to base treatment decisions. Therefore, therapy for mucosal melanoma presents a challenge. Ideally, the goals of local therapy are to achieve complete local excision with wide margins and removal of involved lymph nodes. Achieving wide surgical margins is difficult in tumors close to vital organs; therefore, local recurrences are common. Adjuvant radiation to the tumor bed or to the draining lymph node has been advocated by some clinicians.242 The specific role of adjuvant interferon as it applies to mucosal sites is unclear and, given the marginal benefit of such therapy in general, may best be deferred. Chemotherapy may have a palliative role in these patients, and responses to systemic chemotherapy and biochemotherapy have been described.243,244 Currently, several novel signal transduction inhibitors are being developed to treat metastatic melanoma based on genetic abnormalities commonly noted in dermal melanoma. One example is the development of the raf-kinase inhibitor sorafenib in melanoma based on the presence of activating mutations of the MAP kinase/ras pathway.245 Because these mutations are rarely found in these tumors, it is unclear whether such agents would be effective in mucosal melanoma. MELANOMA OF UNKNOWN PRIMARY LESION Approximately 2% to 4% of all patients with melanoma246-248 and 9% of patients with melanoma with metastatic lymph node involvement249 do not have an identifiable primary Mayo Clin Proc.

•

lesion. The predominant site of involvement tends to be the axilla, and most patients are males.246,249 However, in females, there appears to be a greater preponderance of metastases in the extremities, consistent with the pattern of primary melanomas.248,250 It is unknown whether these clinical settings represent a regressed primary lesion or a primary tumor originating in a typically metastatic site. A few patients with this presentation report regression of a pigmented nevus.251 Despite the presumed presence of a primary undetected lesion, the 5-year survival rate when lymph node metastases are resected is 40% to 55%246,248,249,251,252 and as high as 85% for in-transit or cutaneous metastases that are resected.248 Indeed, at least one series showed a survival advantage when a primary tumor could not be located.251 Patients who present with widespread or visceral metastases, however, have an equally poor prognosis as those with known primary tumors, with survival measured in a few months.246,248 However, when a patient presents with skin or lymphatic metastases from melanoma, an aggressive search for the primary lesion is indicated to remove all disease, with dermatologic examination mandatory and ophthalmic examination recommended, especially for liver metastases.248 If possible, all underlying disease should be surgically resected given the possibility of long-term survival. In addition, PET is a potential option for initial staging, although is unlikely to locate the primary tumor.253 Management for patients with lymph node metastases in one nodal basin should be considered similar to that for patients with a known primary lesion. Patients with multiple areas of involvement or visceral disease should be managed as those with metastatic melanoma. If disease can be resected, interferon or GM-CSF therapy can be considered, as can enrollment in a clinical trial if the patient is eligible. CONCLUSION The key factor in the management of patients with melanoma is the recognition of the need for a dedicated cadre of clinicians, researchers, and statisticians to deal with these patients and their families. This disease is too complicated, too unpredictable, and too deadly to be managed without comprehensive prospective clinical trials. The Mayo Clinic has established some suggested practice guidelines (Table 5), but questions still remain. So what has been accomplished? Where have we come during the past decades? The advances in the management of patients with metastatic melanoma have been frustratingly slow. However, we are now poised on the cusp of treatment such as targeted molecules and “designer

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

507

MALIGNANT MELANOMA IN THE 21ST CENTURY

TABLE 5. Mayo Clinic Suggested Practice Guidelines* Clinical follow-up Primary treatment approach Imaging

Systemic therapy

Interval

Laboratory or imaging tests

Stage

Surgical therapy

I (A and B)

Wide local excision. SLN biopsy is recommended for depths of ≥1 mm, if ulceration is present, or if suspicion of regional disease is high. If SLN biopsy result is positive, proceed with lymph node dissection

No

None (consider clinical trials)

Comprehensive history and physical examination, with special emphasis on the skin and lymph areas every 3-4 mo for year 1, every 6 mo for year 2, and yearly thereafter up to year 5; yearly thereafter as clinically indicated. Patient should be seen by a dermatologist annually for life

At discretion of treating physician

II (A, B, and C)

Wide local excision, with SLN biopsy; if SLN biopsy result is positive, proceed with lymph node dissection

Further imaging as clinically indicated (PET, CT, MRI, chest x-ray examination)

None (consider clinical trials)

Comprehensive history and physical examination, with special emphasis on the skin and lymph areas every 3-4 mo for years 1-3, every 6 mo for years 4 and 5, and yearly thereafter as clinically indicated. Patient should be seen by a dermatologist annually for life

CBC, chemistry panel, and LDH

III (A, B, and C)

Wide local excision followed by SLN biopsy or elective lymph node dissection for clinically involved regional lymph nodes; if SLN biopsy result is positive, proceed with lymph node dissection

Further imaging with PET and/or CT should be considered

IIIA (consider clinical trials); IIIB (adjuvant high-dose interferon alfa for 1 y [controversial]); IIIC (highdose interferon for 1 y [controversial] or low-dose GM-CSF for 1 y [controversial])

Comprehensive history and physical examination, with special emphasis on the skin and lymph areas every 3-4 mo for years 1-3, every 6 mo for years 4 and 5, and yearly thereafter as clinically indicated. Patient should be seen by a dermatologist annually for life

CBC, chemistry panel, LDH; additionally: IIIA–none; IIIB—if prior PET and/or CT for further staging, repeated scanning at physician’s discretion. IIIC–additional PET and/or CT every 3-6 mo for first 5 y and then yearly thereafter

IV

After diagnosis of stage IV disease, decision needs to be made whether patient can be surgically rendered disease free. If possible, complete surgical resection should be considered

Further imaging with PET, CT, and/or MRI highly recommended

No standard therapy for Comprehensive history and stage IV disease and physical examination, with special all patients should be emphasis on the skin and lymph considered for partiareas every 3-4 mo for patients cipation in clinical who are surgically rendered NED trials. For patients and are not proceeding with further who are surgically adjuvant therapy. For all patients resectable to NED, receiving adjuvant or palliative consider adjuvant therapy, frequency of follow-up determined by the regimen GM-CSF.128 For patients ineligible for prescribed and left to discretion surgery and/or cliniof treating physician cal trials, the following palliative therapy options may be offered: (1) interleukin 2, (2) temozolomide or dacarbazine,136 (3) paclitaxel and carboplatin180-182

CBC, chemistry panel, LDH; repeated PET and/or CT every 2-4 mo for the first 5 y and then yearly thereafter for patients rendered NED (high risk of relapse). For all patients receiving adjuvant or palliative therapy, frequency of repeated scanning determined by regimen prescribed and left to discretion of treating physician

*Practice guidelines are institution specific and not exclusively evidence based. CBC = complete blood cell count; CT = computed tomography; GM-CSF = granulocyte-macrophage colony-stimulating factor; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; NED = no evidence of disease; PET = positron emission tomography; SLN = surgical lymph node.

drugs.” These agents have the capacity to affect the process of carcinogenesis in a targeted manner and tap into and unravel the mystery of the immune system as it relates to the control of melanoma. It is highly likely that within the next decade we will bring to the bedside creative, innovative, and relatively nontoxic management for these individuals. 508

Mayo Clin Proc.

•

An anonymous author once made the comment, “The best way to predict the future is to create the future.” With this phrase in mind, with the interest and the commitment of dedicated clinicians, researchers, and scientists, we are creating a future that is positive and hopeful for individuals dealing with malignant melanoma. The future is not down the road. The future is today. The future is now….

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

MALIGNANT MELANOMA IN THE 21ST CENTURY

REFERENCES 1. Markovic SN, Erickson LA, Rao RD, et al, Melanoma Study Group of the Mayo Clinic Cancer Center. Malignant melanoma in the 21st century, part 1: epidemiology, risk factors, screening, prevention, and diagnosis. Mayo Clin Proc. 2007;82:364-380. 2. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001;19:3622-3634. 3. Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19:3635-3648. 4. Allen AC, Spitz S. Malignant melanoma: a clinicopathological analysis of the criteria for diagnosis and prognosis. Cancer. 1953;6:1-45. 5. Lund RH, Ihnen M. Malignant melanoma: clinical and pathologic analysis of 93 cases: is prophylactic lymph node dissection indicated? Surgery. 1955;38:652-659. 6. Lane N, Lattes R, Malm J. Clinicopathological correlations in a series of 117 malignant melanomas of the skin of adults. Cancer. 1958;11:1025-1043. 7. Petersen NC, Bodenham DC, Lloyd OC. Malignant melanomas of the skin: a study of the origin, development, aetiology, spread, treatment, and prognosis. I. Br J Plast Surg. 1962;15:49-94. 8. Mehnert JH, Heard JL. Staging of malignant melanomas by depth of invasion: a proposed index to prognosis. Am J Surg. 1965;110:168-176. 9. Clark WH Jr, From L, Bernardino EA, Mihm MC. The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res. 1969;29:705-727. 10. Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg. 1970;172:902-908. 11. Balch CM, Murad TM, Soong SJ, Ingalls AL, Halpern NB, Maddox WA. A multifactorial analysis of melanoma: prognostic histopathological features comparing Clark’s and Breslow’s staging methods. Ann Surg. 1978;188:732742. 12. Balch CM, Soong S, Ross MI, et al, Intergroup Melanoma Surgical Trial. Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Ann Surg Oncol. 2000;7:87-97. 13. Balch CM, Murad TM, Soong SJ, Ingalls AL, Richards PC, Maddox WA. Tumor thickness as a guide to surgical management of clinical stage I melanoma patients. Cancer. 1979;43:883-888. 14. Clark WH Jr, Elder DE, Guerry D IV, et al. Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst. 1989;81:18931904. 15. Barnhill RL, Fine JA, Roush GC, Berwick M. Predicting five-year outcome for patients with cutaneous melanoma in a population-based study [published correction appears in Cancer. 1997;79:423]. Cancer. 1996;78:427-432. 16. Garbe C, Buttner P, Bertz J, et al. Primary cutaneous melanoma: identification of prognostic groups and estimation of individual prognosis for 5093 patients. Cancer. 1995;75:2484-2491. 17. Rigel DS, Rogers GS, Friedman RJ. Prognosis of malignant melanoma. Dermatol Clin. 1985;3:309-314. 18. Retsas S, Henry K, Mohammed MQ, MacRae K. Prognostic factors of cutaneous melanoma and a new staging system proposed by the American Joint Committee on Cancer (AJCC): validation in a cohort of 1284 patients. Eur J Cancer. 2002;38:511-516. 19. Sondergaard K, Schou G. Prognostic factors in primary cutaneous malignant melanoma. Am J Dermatopathol. 1985;7(suppl):1-4. 20. Sondergaard K, Schou G. Survival with primary cutaneous malignant melanoma, evaluated from 2012 cases: a multivariate regression analysis. Virchows Arch A Pathol Anat Histopathol. 1985;406:179-195. 21. Sondergaard K, Schou G. Therapeutic and clinico-pathological factors in the survival of 1,469 patients with primary cutaneous malignant melanoma in clinical stage I: a multivariate regression analysis. Virchows Arch A Pathol Anat Histopathol. 1985;408:249-258. 22. Stidham KR, Johnson JL, Seigler HF. Survival superiority of females with melanoma: a multivariate analysis of 6383 patients exploring the significance of gender in prognostic outcome. Arch Surg. 1994;129:316-324. 23. Lock-Andersen J, Hou-Jensen K, Hansen JP, Jensen NK, Sogaard H, Andersen PK. Observer variation in histological classification of cutaneous malignant melanoma. Scand J Plast Reconstr Surg Hand Surg. 1995;29:141148. 24. Buzaid AC, Ross MI, Balch CM, et al. Critical analysis of the current American Joint Committee on Cancer staging system for cutaneous melanoma and proposal of a new staging system. J Clin Oncol. 1997;15:1039-1051. 25. Balch CM, Soong SJ, Murad TM, Ingalls AL, Maddox WA. A multifactorial analysis of melanoma, II: prognostic factors in patients with stage I (localized) melanoma. Surgery. 1979;86:343-351. 26. Cascinelli N, Marubini E, Morabito A, Bufalino R. Prognostic factors for stage I melanoma of the skin: a review. Stat Med. 1985;4:265-278.

Mayo Clin Proc.

•

27. Marghoob AA, Koenig K, Bittencourt FV, Kofp AW, Bart RS. Breslow thickness and Clark level in melanoma: support for including level in pathology reports and in American Joint Committee on Cancer Staging. Cancer. 2000;88:589-595. 28. Balch CM, Buzaid AC, Atkins MB, et al. A new American Joint Committee on Cancer staging system for cutaneous melanoma. Cancer. 2000;88:1484-1491. 29. Day CL Jr, Harrist TJ, Gorstein F, et al. Malignant melanoma: prognostic significance of “microscopic satellites” in the reticular dermis and subcutaneous fat. Ann Surg. 1981;194:108-112. 30. Harrist TJ, Rigel DS, Day CL Jr, et al. “Microscopic satellites” are more highly associated with regional lymph node metastases than is primary melanoma thickness. Cancer. 1984;53:2183-2187. 31. Leon P, Daly JM, Synnestvadt M, Schultz DJ, Elder DE, Clark WH Jr. The prognostic implications of microscopic satellites in patients with clinical stage I melanoma. Arch Surg. 1991;126:1461-1468. 32. Rao UN, Ibrahim J, Flaherty LE, Richards J, Kirkwood JM. Implications of microscopic satellites of the primary and extracaspular lymph node spread in patients with high-risk melanoma: pathologic corollary of Eastern Cooperative Oncology Group Trial E1690. J Clin Oncol. 2002;20:2053-2057. 33. Gershenwald JE, Thompson W, Mansfield PF, et al. Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol. 1999;17:976-983. 34. Balch CM, Buzaid AC, Soong SJ, et al. New TNM melanoma staging system: linking biology and natural history to clinical outcomes. Semin Surg Oncol. 2003;21:43-52. 35. Yan S, Brennick JB. False-positive rate of the immunoperoxidase stains for MART1/MelanA in lymph nodes. Am J Surg Pathol. 2004;28:596-600. 36. Clark WH Jr, Elder DE, Guerry D IV, Epstein MN, Greene MH, Van Horn M. A study of tumor progression: the precursor lesions of superficial spreading and nodular melanoma. Hum Pathol. 1984;15:1147-1165. 37. Crowson AN, Magro CM, Mihm MC Jr, eds. The Melanocytic Proliferations: A Comprehensive Textbook of Pigmented Lesions. New York, NY: Wiley-Liss; 2001. 38. Elder DE, Guerry D IV, Epstein MN, et al. Invasive malignant melanomas lacking competence for metastasis. Am J Dermatopathol. 1984;6(suppl):5561. 39. Guerry D IV, Synnestvedt M, Elder DE, Schultz D. Lessons from tumor progression: the invasive radial growth phase of melanoma is common, incapable of metastasis, and indolent. J Invest Dermatol. 1993;100:342S-345S. 40. Lefevre M, Vergier B, Balme B, et al. Relevance of vertical growth pattern in thin level II cutaneous superficial spreading melanomas. Am J Surg Pathol. 2003;27:717-724. 41. Oliveira Filho RS, Ferreira LM, Biasi LJ, Enokihara MM, Paiva GR, Wagner J. Vertical growth phase and positive sentinel node in thin melanoma. Braz J Med Biol Res. 2003 Mar;36:347-350. Epub 2003 Mar 7. 42. Taran JM, Heenan PJ. Clinical and histologic features of level 2 cutaneous malignant melanoma associated with metastasis. Cancer. 2001;91:18221825. 43. Otto FJ, Goldmann T, Biess B, Lippold A, Suter L, Westhoff U. Prognostic classification of malignant melanomas by combining clinical, histological, and immunohistochemical parameters. Oncology. 1999;56:208-214. 44. Day CL Jr, Mihm MC Jr, Lew RA, et al. Prognostic factors for patients with clinical stage I melanoma of intermediate thickness (1.51-3.39 mm): a conceptual model for tumor growth and metastasis. Ann Surg. 1982;195:3543. 45. Byers HR, Bhawan J. Pathologic parameters in the diagnosis and prognosis of primary cutaneous melanoma. Hematol Oncol Clin North Am. 1998;12:717-735. 46. Barnhill RL, Katzen J, Spatz A, Fine J, Berwick M. The importance of mitotic rate as a prognostic factor for localized cutaneous melanoma. J Cutan Pathol. 2005;32:268-273. 47. Azzola MF, Shaw HM, Thompson JF, et al. Tumor mitotic rate is a more powerful prognostic indicator than ulceration in patients with primary cutaneous melanoma: an analysis of 3661 patients from a single center. Cancer. 2003;97:1488-1498. 48. Karjalainen JM, Eskelinen MJ, Nordling S, Lipponen PK, Alhava EM, Kosma VM. Mitotic rate and S-phase fraction as prognostic factors in stage I cutaneous malignant melanoma. Br J Cancer. 1998;77:1917-1925. 49. Massi D, Borgobnoni L, Franchi A, Martini L, Reali UM, Santucci M. Thick cutaneous malignant melanoma: a reappraisal of prognostic factors. Melanoma Res. 2000;10:153-164. 50. Gimotty PA, Guerry D, Ming ME, et al. Thin primary cutaneous malignant melanoma: a prognostic tree for 10-year metastasis is more accurate than American Joint Committee on Cancer staging [published correction appears in J Clin Oncol. 2005;23:656]. J Clin Oncol. 2004 Sep 15;22:3668-3676. Epub 2004 Aug 9.

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

509

MALIGNANT MELANOMA IN THE 21ST CENTURY

51. Gimotty PA, Van Belle P, Elder DE, et al. Biologic and prognostic significance of dermal Ki67 expression, mitoses, and tumorigenicity in thin invasive cutaneous melanoma. J Clin Oncol. 2005;23:8048-8056. 52. Kesmodel SB, Karakousis GC, Botbyl JD, et al. Mitotic rate as a predictor of sentinel lymph node positivity in patients with thin melanomas. Ann Surg Oncol. 2005 Jun;12:449-458. Epub 2005 Apr 19. 53. Karakousis GC, Gimotty PA, Botbyl JD, et al. Predictors of regional nodal disease in patients with thin melanomas. Ann Surg Oncol. 2006 Apr; 13:533-541. Epub 2006 Mar 7. 54. Mraz-Gernhard S, Sagebiel RW, Kashani-Sabet M, Miller JR III, Leong SP. Prediction of sentinel lymph node micrometastasis by histological features in primary cutaneous malignant melanoma. Arch Dermatol. 1998;134:983987. 55. Blessing K, McLaren KM. Histological regression in primary cutaneous melanoma: recognition, prevalence and significance. Histopathology. 1992;20: 315-322. 56. Ronan SG, Eng AM, Briele HA, Shioura NN, Gas Gupta TK. Thin malignant melanomas with regression and metastases. Arch Dermatol. 1987; 123:1326-1330. 57. Paladugu RR, Yonemoto RH. Biologic behavior of thin malignant melanomas with regressive changes. Arch Surg. 1983;118:1-44. 58. Naruns PL, Nizze JA, Cochran AJ, Lee MB, Morton DL. Recurrence potential of thin primary melanomas. Cancer. 1986;57:545-548. 59. Blessing K, McLaren KM, McLean A, Davidson P. Thin malignant melanomas (less than 1.5 mm) with metastasis: a histological study and survival analysis. Histopathology. 1990;17:389-395. 60. Guitart J, Lowe L, Piepkorn M, et al. Histological characteristics of metastasizing thin melanomas: a case-control study of 43 cases. Arch Dermatol. 2002;138:603-608. 61. Slingluff CL Jr, Vollmer RT, Reintgen DS, Seigler HF. Lethal “thin” malignant melanoma: identifying patients at risk. Ann Surg. 1988;208:150161. 62. Zettersten E, Sagebiel RW, Miller JR III, Tallapureddy S, Leong SP, Kashani-Sabet M. Prognostic factors in patients with thick cutaneous melanoma (>4 mm). Cancer. 2002;94:1049-1056. 63. Straume O, Akslen LA. Independent prognostic importance of vascular invasion in nodular melanomas. Cancer. 1996;78:1211-1219. 64. Barnhill R, Dy K, Lugassy C. Angiotropism in cutaneous melanoma: a prognostic factor strongly predicting risk for metastasis. J Invest Dermatol. 2002;119:705-706. 65. Barnhill RL, Lugassy C. Angiotropic malignant melanoma and extravascular migratory metastasis: description of 36 cases with emphasis on a new mechanism of tumour spread. Pathology. 2004;36:485-490. 66. Lugassy C, Haroun RI, Brem H, et al. Pericytic-like angiotropism of glioma and melanoma cells. Am J Dermatopathol. 2002;24:473-478. 67. Clemente CG, Mihm MC Jr, Bufalina R, Zurrida S, Collini P, Cascinelli N. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer. 1996;77:1303-1310. 68. Elder DE, Guerry D IV, VanHorn M, et al. The role of lymph node dissection for clinical stage malignant melanoma of intermediate thickness (1.51-3.99 mm). Cancer. 1985;56:413-418. 69. Tuthill RJ, Undger JM, Liu PY, Flaherty LE, Sondak VK, Southwest Oncology Group. Risk assessment in localized primary cutaneous melanoma: a Southwest Oncology Group study evaluating nine factors and a test of the Clark logistic regression prediction model. Am J Clin Pathol. 2002;118:504511. 70. Masback A, Olsson H, Westerdahl J, Ingvar C, Jonsson N. Prognostic factors in invasive cutaneous malignant melanoma: a population-based study and review. Melanoma Res. 2001;11:435-445. 71. Barnhill RL, Piepkorn M, Busam KJ. Pathology of Melanocytic Nevi and Malignant Melanoma. 2nd ed. New York, NY: Springer; 2004:238-394. 72. McGovern VJ, Cochran AJ, Van der Esch EP, Little JH, MacLennan R. The classification of malignant melanoma, its histological reporting and registration: a revision of the 1972 Sydney classification. Pathology. 1986;18:1221. 73. Pack GT, Miller TR. Metastatic melanoma with indeterminate primary site: report of two instances of long-term survival. JAMA. 1961;176:55-56. 74. Brogelli L, Reali UM, Moretti S, Urso C. The prognostic significance of histologic regression in cutaneous melanoma [published correction appears in Melanoma Res. 1992;2:213]. Melanoma Res. 1992;2:87-91. 75. Fontaine D, Parkhill W, Greer W, Walsh N. Partial regression of primary cutaneous melanoma: is there an association with sub-clinical sentinel lymph node metastasis? Am J Dermatopathol. 2003;25:371-376. 76. Kelly JW, Sagebiel RW, Blois MS. Regression in malignant melanoma: a histologic feature without independent prognostic significance. Cancer. 1985;56:2287-2291. 77. Lugassy C, Kleinman HK, Fernandez PM, et al. Human melanoma cell migration along capillary-like structures in vitro: a new dynamic model for

510

Mayo Clin Proc.

•

studying extravascular migratory metastasis. J Invest Dermatol. 2002;119:703704. 78. Melanoma of the skin. In: Green FL, Page DL, Fleming ID, et al, eds. AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer; 2002:209220. 79. Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma [published correction appears in N Engl J Med. 2004;351:2461]. N Engl J Med. 2004;351:998-1012. 80. Miranda EP, Gertner M, Wall J, et al. Routine imaging of asymptomatic melanoma patients with metastasis to sentinel lymph nodes rarely identifies systemic disease. Arch Surg. 2004;139:831-836. 81. Wagner JD, Schauwecker D, Davidson D, et al. Inefficacy of F-18 fluorodeoxy-D-glucose-positron emission tomography scans for initial evaluation in early-stage cutaneous melanoma. Cancer. 2005;104:570-579. 82. Brady MS, Akhurst T, Spanknebel K, et al. Utility of preoperative [(18)]F fluorodeoxyglucose-positron emission tomography scanning in highrisk melanoma patients. Ann Surg Oncol. 2006 Apr;13:525-532. Epub 2006 Feb 15. 83. Veronesi U, Cascinelli N, Adamus J, et al. Thin stage I primary cutaneous malignant melanoma: comparison of excision with margins of 1 or 3 cm [published correction appears in N Engl J Med. 1991;325:292]. N Engl J Med. 1988;318:1159-1162. 84. Heaton KM, Sussman JJ, Gershenwald JE, et al. Surgical margins and prognostic factors in patients with thick (>4 mm) primary melanoma. Ann Surg Oncol. 1998;5:322-328. 85. Pennington BE, Leffel DJ. Mohs micrographic surgery: established uses and emerging trends. Oncology (Williston Park). 2005;19:1165-1171. 86. Karakousis CP, Goumas W, Rao U, Driscoll DL. Axillary node dissection in malignant melanoma. Am J Surg. 1991;162:202-207. 87. Balch CM, Soong SJ, Smith T, et al, Investigators from the Intergroup Melanoma Surgical Trial. Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol. 2001;8:101-108. 88. Reintgen DS, Cox EB, McCarty KS Jr, Vollmer RT, Seigler HF. Efficacy of elective lymph node dissection in patients with intermediate thickness primary melanoma. Ann Surg. 1983;198:379-385. 89. McCarthy WH, Shaw HM, Milton GW. Efficacy of elective lymph node dissection in 2,347 patients with clinical stage I malignant melanoma. Surg Gynecol Obstet. 1985;161:575-580. 90. Balch CM, Soong SJ, Milton GW, et al. A comparison of prognostic factors and surgical results in 1,786 patients with localized (stage I) melanoma treated in Alabama, USA, and New South Wales, Australia. Ann Surg. 1982;196:677-684. 91. Sim FH, Taylor WF, Pritchard DJ, Soule EH. Lymphadenectomy in the management of stage I malignant melanoma: a prospective randomized study. Mayo Clin Proc. 1986;61:697-705. 92. Veronesi U, Adamus J, Bandiera DC, et al. Inefficacy of immediate node dissection in stage 1 melanoma of the limbs. N Engl J Med. 1977;297: 627-630. 93. Cascinelli N, Morabito A, Santinami M, MacKie RM, Belli F, WHO Melanoma Programme. Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. Lancet. 1998;351:793796. 94. Balch CM, Soong SJ, Bartolucci AA, et al. Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger. Ann Surg. 1996;224:255-263. 95. Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127:392399. 96. Albertini JJ, Cruse CW, Raraport D, et al. Intraoperative radio-lymphoscintigraphy improves sentinel lymph node identification for patients with melanoma. Ann Surg. 1996;223:217-224. 97. Thompson JF, McCarthy WH, Bosch CM, et al. Sentinel lymph node status as an indicator of the presence of metastatic melanoma in regional lymph nodes. Melanoma Res. 1995;5:255-260. 98. Norman J, Cruse CW, Espinosa C, et al. Redefinition of cutaneous lymphatic drainage with the use of lymphoscintigraphy for malignant melanoma. Am J Surg. 1991;162:432-437. 99. Joseph E, Brobeil A, Glass F, et al. Results of complete lymph node dissection in 83 melanoma patients with positive sentinel nodes. Ann Surg Oncol. 1998;5:119-125. 100. Morton DL, Thompson JF, Essner R, et al, Multicenter Selective Lymphadenectomy Trial Group. Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: a multicenter trial. Ann Surg. 1999;230:453-463. 101. Morton DL, Chan AD. Current status of intraoperative lymphatic mapping and sentinel lymphadenectomy for melanoma: is it standard of care? J Am Coll Surg. 1999;189:214-223.

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

MALIGNANT MELANOMA IN THE 21ST CENTURY

102. Leong SP, Steinmetz I, Habib FA, et al. Optimal selective sentinel lymph node dissection in primary malignant melanoma. Arch Surg. 1997;132:666-672. 103. Lee JH, Essner R, Torisu-Itakura H, Wanek L, Wang H, Morton DL. Factors predictive of tumor-positive nonsentinel lymph nodes after tumorpositive sentinel lymph node dissection for melanoma. J Clin Oncol. 2004;22:3677-3684. 104. Karakousis CP, Grigoropoulos P. Sentinel node biopsy before and after wide excision of the primary melanoma. Ann Surg Oncol. 1999;6:785-789. 105. Essner R, Chung MH, Bleicher R, Hsueh E, Wanek L, Morton DL. Prognostic implications of thick (≥4-mm) melanoma in the era of intraoperative lymphatic mapping and sentinel lymphadenectomy. Ann Surg Oncol. 2002;9:754-761. 106. Carlson GW, Murray DR, Hestley A, Staley CA, Lyles RH, Cohen C. Sentinel lymph node mapping for thick (≥4-mm) melanoma: should we be doing it? Ann Surg Oncol. 2003;10:408-415. 107. Ferrone CR, Panageas KS, Busam K, Brady MS, Coit DG. Multivariate prognostic model for patients with thick cutaneous melanoma: importance of sentinel lymph node status. Ann Surg Oncol. 2002;9:637-645. 108. Shivers SC, Wang X, Li W, et al. Molecular staging of malignant melanoma: correlation with clinical outcome. JAMA. 1998;280:1410-1415. 109. Kammula US, Ghossein R, Bhattacharya S, Coit DG. Serial follow-up and the prognostic significance of reverse transcriptase-polymerase chain reaction–staged sentinel lymph nodes from melanoma patients. J Clin Oncol. 2004;22:3989-3996. 110. Cormier JN, Xing Y, Ding M, et al. Population-based assessment of surgical treatment trends for patients with melanoma in the era of sentinel lymph node biopsy. J Clin Oncol. 2005;23:6054-6062. 111. Morton DL, Thompson JF, Cochran AJ, Essner R, Elashoff R, Group MSLT. Interim results of the Multicenter Selective Lymphadenectomy Trial (MSLT-I) in clinical stage I melanoma [abstract]. J Clin Oncol. 2005; 23(suppl):710s. Abstract 7500. 112. Essner R, Lee JH, Wanek LA, Itakura H, Morton DL. Contemporary surgical treatment of advanced-stage melanoma. Arch Surg. 2004;139:961-966. 113. Meyer T, Merkel S, Goehl J, Hohenberger W. Surgical therapy for distant metastases of malignant melanoma. Cancer. 2000;89:1983-1991. 114. Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alpha-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14:7-17. 115. Creagan ET, Dalton RJ, Ahmann DL, et al. Randomized, surgical adjuvant clinical trial of recombinant interferon alfa-2a in selected patients with malignant melanoma. J Clin Oncol. 1995;13:2776-2783. 116. Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol. 2000;18:2444-2458. 117. Stoutenburg JP, Schrope B, Kaufman HL. Adjuvant therapy for malignant melanoma. Expert Rev Anticancer Ther. 2004;4:823-835. 118. Kirkwood JM, Manola J, Ibrahim J, Sondak V, Ernstoff MS, Rao U, Eastern Cooperative Oncology Group. A pooled analysis of Eastern Cooperative Oncology Group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res. 2004;10:1670-1677. 119. Kirkwood JM, Ibrahim JG, Sosman JA, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol. 2001;19:2370-2380. 120. Gogas H, Ioannovich J, Dafni U, et al. Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med. 2006;354:709-718. 121. Cascinelli N, Bufalino R, Morabito A, Mackie R. Results of adjuvant interferon study in WHO melanoma programme. Lancet. 1994;343:913-914. 122. Kleeberg UR, Suciu S, Brocker EB, et al, EORTC Melanoma Group in cooperation with the German Cancer Society (DKG). Final results of the EORTC 18871/DKG 80-1 randomised phase III trial: rIFN-α2b versus rIFN-γ versus ISCADOR M versus observation after surgery in melanoma patients with either high-risk primary (thickness >3 mm) or regional lymph node metastasis. Eur J Cancer. 2004;40:390-402. 123. Rusciani L, Petraglia S, Alotto M, Calvieri S, Vezzoni G. Postsurgical adjuvant therapy for melanoma: evaluation of a 3-year randomized trial with recombinant interferon-alpha after 3 and 5 years of follow-up. Cancer. 1997;79:2354-2360. 124. Grob JJ, Dreno B, de la Salmoniere P, et al, French Cooperative Group on Melanoma. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. Lancet. 1998;351:1905-1910. 125. Pehamberger H, Soyer HP, Steiner A, et al, Austrian Malignant Melanoma Cooperative Group. Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. J Clin Oncol. 1998;16:1425-1429.

Mayo Clin Proc.

•

126. Eggermont AM, Suciu S, MacKie R, et al, EORTC Melanoma Group. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet. 2005;366:1189-1196. 127. Hauschild A, Weichenthal M, Balda BR, et al. Prospective randomized trial of interferon alfa-2b and interleukin-2 as adjuvant treatment for resected intermediate- and high-risk primary melanoma without clinically detectable node metastasis. J Clin Oncol. 2003;21:2883-2888. 128. Spitler LE, Grossbard ML, Ernstoff MS, et al. Adjuvant therapy of stage III and IV malignant melanoma using granulocyte-macrophage colony-stimulating factor. J Clin Oncol. 2000;18:1614-1621. 129. Berd D, Maguire HC Jr, Schuchter LM, et al. Autologous haptenmodified melanoma vaccine as postsurgical adjuvant treatment after resection of nodal metastases. J Clin Oncol. 1997;15:2359-2370. 130. Bystryn JC. Clinical activity of a polyvalent melanoma antigen vaccine. Recent Results Cancer Res. 1995;139:337-348. 131. DiFronzo LA, Gupta RK, Essner R, et al. Enhanced humoral immune response correlates with improved disease-free and overall survival in American Joint Committee on Cancer stage II melanoma patients receiving adjuvant polyvalent vaccine. J Clin Oncol. 2002;20:3242-3248. 132. Berd D, Sato T, Maguire HC Jr, Kairys J, Mastrangelo MJ. Immunopharmacologic analysis of an autologous, hapten-modified human melanoma vaccine. J Clin Oncol. 2004 Feb 1;22:403-415. Epub 2003 Dec 22. 133. Balch CM, Sober AJ, Soong SJ, Gershenwald JE, AJCC Melanoma Staging Committee. The new melanoma staging system. Semin Cutan Med Surg. 2003;22:42-54. 134. Carter SK, Friedman MA. 5-(3,3-dimethyl-l-triazeno)-imidazole-4carboxamide (DTIC, DIC, NSC-45388): a new antitumor agent with activity against malignant melanoma. Eur J Cancer. 1972;8:85-92. 135. Bellett RE, Mastrangelo MJ, Laucius JF, Bodurtha AJ. Randomized prospective trial of DTIC (NSC-45388) alone versus BCNU (NSC-409962) plus vincristine (NSC-67574) in the treatment of metastatic malignant melanoma. Cancer Treat Rep. 1976;60:595-600. 136. Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma [published correction appears in J Clin Oncol. 2000;18:2351]. J Clin Oncol. 2000;18:158-166. 137. Mule JJ, Ettinghausen SE, Spiess PJ, Shu S, Rosenberg SA. Antitumor efficacy of lymphokine-activated killer cells and recombinant interleukin-2 in vivo: survival benefit and mechanisms of tumor escape in mice undergoing immunotherapy. Cancer Res. 1986;46:676-683. 138. Topalian SL, Rosenberg SA. Therapy of cancer using the adoptive transfer of activated killer cells and interleukin 2. Acta Haematol. 1987;78(suppl):7576. 139. Papa MZ, Mule JJ, Rosenberg SA. Antitumor efficacy of lymphokineactivated killer cells and recombinant interleukin 2 in vivo: successful immunotherapy of established pulmonary metastases from weakly immunogenic and nonimmunogenic murine tumors of three distinct histological types. Cancer Res. 1986;46:4973-4978. 140. Lotze MT, Rosenberg SA. Results of clinical trials with the administration of interleukin 2 and adoptive immunotherapy with activated cells in patients with cancer. Immunobiology. 1986;172:420-437. 141. Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA. Lymphokineactivated killer cell phenomenon: lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med. 1982;155:1823-1841. 142. Rosenberg SA, Lotze MT, Yang JC, et al. Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg. 1989;210:474-484. 143. Rosenberg SA, Lotze MT, Yang JC, et al. Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer [published correction appears in J Natl Cancer Inst. 1993;85:1091]. J Natl Cancer Inst. 1993;85:622-632. 144. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995;13: 688-696. 145. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17:2105-2116. 146. Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000;6(suppl):S11-S14. 147. Atkins MB. Interleukin-2 in metastatic melanoma: establishing a role. Cancer J Sci Am. 1997;3(suppl):S7-S8. 148. Atkins MB. Interleukin-2 in metastatic melanoma: what is the current role? Cancer J Sci Am. 2000;6(suppl):S8-S10.

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

511

MALIGNANT MELANOMA IN THE 21ST CENTURY

149. Buzaid AC, Legha SS. Combination of chemotherapy with interleukin2 and interferon-alfa for the treatment of advanced melanoma. Semin Oncol. 1994;21(suppl):23-28. 150. Legha SS, Ring S, Eton O, Bedikian A, Plager C, Papadopoulos N. Development and results of biochemotherapy in metastatic melanoma: the University of Texas M.D. Anderson Cancer Center experience. Cancer J Sci Am. 1997;3(suppl):S9-S15. 151. Atkins MB. The treatment of metastatic melanoma with chemotherapy and biologics. Curr Opin Oncol. 1997;9:205-213. 152. Legha SS, Ring S, Bedikian A, et al. Treatment of metastatic melanoma with combined chemotherapy continuing cisplatin, vinblastine and dacarbazine (CVD) and biotherapy using interleukin-2 and interferon-alpha. Ann Oncol. 1996;7:827-835. 153. Legha SS, Ring S, Eton O, et al. Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma. J Clin Oncol. 1998;16:1752-1759. 154. Legha SS. Durable complete responses in metastatic melanoma treated with interleukin-2 in combination with interferon alpha and chemotherapy. Semin Oncol. 1997;24(suppl):S39-S43. 155. Eton O, Legha SS, Bedikian AY, et al. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol. 2002;20:2045-2052. 156. Atkins MB. Cytokine-based therapy and biochemotherapy for advanced melanoma. Clin Cancer Res. 2006;12:2353s-2358s. 157. Hsueh EC, Essner R, Foshag LJ, et al. Prolonged survival after complete resection of disseminated melanoma and active immunotherapy with a therapeutic cancer vaccine. J Clin Oncol. 2002;20:4549-4554. 158. Mitchell MS, Kan-Mitchell J, Kempf RA, Harel W, Shau HY, Lind S. Active specific immunotherapy for melanoma: phase I trial of allogeneic lysates and a novel adjuvant. Cancer Res. 1988;48:5883-5893. 159. Mitchell MS, Harel W, Kempf RA, et al. Active-specific immunotherapy for melanoma. J Clin Oncol. 1990;8:856-869. 160. Sondak VK, Liu PY, Tuthill RJ, et al. Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: overall results of a randomized trial of the Southwest Oncology Group. J Clin Oncol. 2002;20:2058-2066. 161. Sosman JA, Sondak VK. Melacine: an allogeneic melanoma tumor cell lysate vaccine. Expert Rev Vaccines. 2003;2:353-368. 162. Sondak VK, Sosman JA. Results of clinical trials with an allogenic melanoma tumor cell lysate vaccine: melacine. Semin Cancer Biol. 2003;13:409-415. 163. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leukovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335-2342. 164. Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006 Jan 1;24:16-24. Epub 2005 Dec 5. 165. Hwu WJ, Krown SE, Menell JH, et al. Phase II study of temozolomide plus thalidomide for the treatment of metastatic melanoma. J Clin Oncol. 2003;21:3351-3356. 166. Hwu WJ, Krown SE, Panageas KS, et al. Temozolomide plus thalidomide in patients with advanced melanoma: results of a dose-finding trial [published correction appears in J Clin Oncol. 2002;20:3361]. J Clin Oncol. 2002;20:2610-2615. 167. Kudva GC, Collins BT, Dunphy FR II. Thalidomide for malignant melanoma. N Engl J Med. 2001;345:1214-1215. 168. Hwu WJ, Raizer J, Panageas KS, Lis E. Treatment of metastatic melanoma in the brain with temozolomide and thalidomide. Lancet Oncol. 2001;2:634-635. 169. Pawlak WZ, Legha SS. Phase II study of thalidomide in patients with metastatic melanoma. Melanoma Res. 2004;14:57-62. 170. Reiriz AB, Richter MF, Fernandes S, et al. Phase II study of thalidomide in patients with metastatic malignant melanoma. Melanoma Res. 2004;14:527-531. 171. Hwu WJ, Lis E, Menell JH, et al. Temozolomide plus thalidomide in patients with brain metastases from melanoma: a phase II study. Cancer. 2005;103:2590-2597. 172. Molina JR, Reid JM, Erlichman C, et al. A phase I and pharmacokinetic study of the selective, non-peptidic inhibitor of matrix metaloproteinase BAY 12-9566 in combination with etoposide and carboplatin. Anticancer Drugs. 2005;16:997-1002. 173. Weng DE, Masci PA, Radka SF, et al. A phase I clinical trial of a ribozyme-based angiogenesis inhibitor targeting vascular endothelial growth factor receptor-1 for patients with refractory solid tumors. Mol Cancer Ther. 2005;4:948-955. 174. Peterson AC, Swiger S, Stadler WM, Medved M, Karczmar G, Gajewski TF. Phase II study of the Flk-1 tyrosine kinase inhibitor SU 5416 in advanced melanoma. Clin Cancer Res. 2004;10:4048-4054.

512

Mayo Clin Proc.

•

175. Kuenen BC, Tabernero J, Baselga J, et al. Efficacy and toxicity of the angiogenesis inhibitors SU5416 as a single agent in patients with advanced renal cell carcinoma, melanoma, and soft tissue sarcoma. Clin Cancer Res. 2003;9:1648-1655. 176. Bartlett JB, Michael A, Clarke IA, et al. Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers. Br J Cancer. 2004;90:955-961. 177. Bhargava P, Marshall JL, Dahut W, et al. A phase I and pharmacokinetic study of squalamine, a novel antiangiogenic agent, in patients with advanced cancers. Clin Cancer Res. 2001;7:3912-3919. 178. Bhargava P, Marshall JL, Rizvi N, et al. A phase I and pharmacokinetic study of TNP-470 administered weekly to patients with advanced cancer. Clin Cancer Res. 1999;5:1989-1995. 179. Margolin K, Longmate J, Baratta T, et al. CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Cancer. 2005;104:1045-1048. 180. Zimpfer-Rechner C, Hofmann U, Figl R, et al. Randomized phase II study of weekly paclitaxel versus paclitaxel and carboplatin as second-line therapy in disseminated melanoma: a multicentre trial of the Dermatologic Cooperative Oncology Group (DeCOG). Melanoma Res. 2003;13:531-536. 181. Hodi FS, Soiffer RJ, Clark J, Finkelstein DM, Haluska FG. Phase II study of paclitaxel and carboplatin for malignant melanoma. Am J Clin Oncol. 2002;25:283-286. 182. Rao RD, Holtan SG, Ingle JN, et al. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer. 2006;106:375-382. 183. Danson S, Lorigan P. Improving outcomes in advanced malignant melanoma: update on systemic therapy. Drugs. 2005;65:733-743. 184. Panka DJ, Wang W, Atkins MB, Mier JW. The Raf inhibitor BAY 439006 (Sorafenib) induces caspase-independent apoptosis in melanoma cells. Cancer Res. 2006;66:1611-1619. 185. Smalley KS, Herlyn M. Targeting intracellular signaling pathways as a novel strategy in melanoma therapeutics. Ann N Y Acad Sci. 2005;1059:16-25. 186. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002 Jun 27;417:949-954. Epub 2002 Jun 9. 187. Brose MS, Volpe P, Feldman M, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 2002;62:6997-7000. 188. Schreck R, Rapp UR. Raf kinases: oncogenesis and drug discovery. Int J Cancer. 2006;119:2261-2271. 189. Hodi FS, Mihm MC, Soiffer RJ, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A. 2003 Apr 15;100:4712-4717. Epub 2003 Apr 7. 190. Ribas A, Camacho LH, Lopez-Berestein G, et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol. 2005 Dec 10;23:8968-8977. Epub 2005 Oct 3. 191. Deiner-West M, Earle JD, Fine SL, et al, Collaborative Ocular Melanoma Study Group. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, II: characteristics of patients enrolled and not enrolled. Arch Ophthalmol. 2001;119:951-965. COMS Report No. 17. 192. Diener-West M, Earle JD, Fine SL, et al, Collaborative Ocular Melanoma Study Group. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, III: initial mortality findings. Arch Ophthalmol. 2001;119:969-982. COMS Report No. 18. 193. Harwood AR, Lawson VG. Radiation therapy for melanomas of the head and neck. Head Neck Surg. 1982;4:468-474. 194. Tsang RW, Liu FF, Wells W, Payne DG. Lentigo maligna of the head and neck: results of treatment by radiotherapy. Arch Dermatol. 1994;130:1008-1012. 195. Schmid-Wendtner MH, Brunner B, Konz B, et al. Fractionated radiotherapy of lentigo maligna and lentigo maligna melanoma in 64 patients. J Am Acad Dermatol. 2000;43:477-482. 196. Johanson CR, Harwood AR, Cummings BJ, Quirt I. 0-7-21 radiotherapy in nodular melanoma. Cancer. 1983;15:226-232. 197. Creagan ET, Cupps RE, Ivins JC, et al. Adjuvant radiation therapy for regional nodal metastases from malignant melanoma: a randomized, prospective study. Cancer. 1978;42:2206-2210. 198. Ang KK, Byers RM, Peters LJ, et al. Regional radiotherapy as adjuvant treatment for head and neck malignant melanoma: preliminary results. Arch Otolaryngol Head Neck Surg. 1990;116:169-172. 199. Ang KK, Peters LJ, Weber RS, et al. Postoperative radiotherapy for cutaneous melanoma of the head and neck region. Int J Radiat Oncol Biol Phys. 1994;30:795-798. 200. Ballo MT, Ang KK. Radiation therapy for malignant melanoma. Surg Clin North Am. 2003;83:323-342. 201. Geara FB, Ang KK. Radiation therapy for malignant melanoma. Surg Clin North Am. 1996;76:1383-1398.

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

MALIGNANT MELANOMA IN THE 21ST CENTURY

202. Ballo MT, Garden AS, Myers JN, et al. Melanoma metastatic to cervical lymph nodes: can radiotherapy replace formal dissection after local excision of nodal disease? Head Neck. 2005;27:718-721. 203. Ballo MT, Strom EA, Zagars GK, et al. Adjuvant irradiation for axillary metastases from malignant melanoma. Int J Radiat Oncol Biol Phys. 2002; 52:964-972. 204. Ballo MT, Gershenwald JE, Zagars GK, et al. Sphincter-sparing local excision and adjuvant radiation for anal-rectal melanoma. J Clin Oncol. 2002;20:4555-4558. 205. Ballo MT, Bonnen MD, Garden AS, et al. Adjuvant irradiation for cervical lymph node metastases from melanoma. Cancer. 2003;97:17891796. 206. Ballo MT, Ang KK. Radiotherapy for cutaneous malignant melanoma: rationale and indications. Oncology (Williston Park). 2004;18:99-107. 207. Ballo MT, Zagars GK, Gershenwald JE, et al. A critical assessment of adjuvant radiotherapy for inguinal lymph node metastases from melanoma. Ann Surg Oncol. 2004;11:1079-1084. 208. Ballo MT, Ross MI, Cormier JN, et al. Combined-modality therapy for patients with regional nodal metastases from melanoma. Int J Radiat Oncol Biol Phys. 2006 Jan 1;64:106-113. Epub 2005 Sep 22. 209. Amozorrutia-Alegria V, Bravo-Ortiz JC, Vazquez-Viveros J, et al. Epidemiological characteristics of retinoblastoma in children attending the Mexican Social Security Institute in Mexico City, 1990-1994. Paediatr Perinat Epidemiol. 2002;16:370-374. 210. Overgaard J, von der Maase H, Overgaard M. A randomized study comparing two high-dose per fraction radiation schedules in recurrent or metastatic malignant melanoma. Int J Radiat Oncol Biol Phys. 1985;11:18371839. 211. Sause WT, Cooper JS, Rush S, et al. Fraction size in external beam radiation therapy in the treatment of melanoma. Int J Radiat Oncol Biol Phys. 1991;20:429-432. 212. Meier S, Baumert BG, Maier T, et al. Survival and prognostic factors in patients with brain metastases from malignant melanoma. Onkologie. 2004; 27:145-149. 213. Singh AD, Kalyani P, Topham A. Estimating the risk of malignant transformation of a choroidal nevus. Ophthalmology. 2005;112:1784-1789. 214. Singh AD, Bergman L, Seregard S. Uveal melanoma: epidemiologic aspects. Ophthalmol Clin North Am. 2005;18:75-84. 215. Infante de German-Ribon R, Singh AD, Arevalo JF, Driebe W, Eskin T. Choroidal melanoma with oculodermal melanocytosis in Hispanic patients. Am J Ophthalmol. 1999;128:251-253. 216. Singh AD, Borden EC. Metastatic uveal melanoma. Ophthalmol Clin North Am. 2005;18:143-150. 217. Singh AD, Kivela T. The collaborative ocular melanoma study. Ophthalmol Clin North Am. 2005;18:129-142. 218. Diener-West M, Reynolds SM, Agugliaro DJ, et al, Collaborative Ocular Melanoma Study Group. Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No. 26. Arch Ophthalmol. 2005;123: 1639-1643. 219. Singh AD, Damato B, Howard P, Harbour JW. Uveal melanoma: genetic aspects. Ophthalmol Clin North Am. 2005;18:85-97. 220. Onken MD, Ehlers JP, Worley LA, Makita J, Yokota Y, Harbour JW. Functional gene expression analysis uncovers phenotypic switch in aggressive uveal melanomas. Cancer Res. 2006;66:4602-4609. 221. Mehaffey MG, Folberg R, Meyer M, et al. Relative importance of quantifying area and vascular patterns in uveal melanomas. Am J Ophthalmol. 1997;123:798-809. 222. Folberg R, Fleck M, Mehaffey MG, et al. Mapping the location of prognostically significant microcirculatory patterns in ciliary body and choroidal melanomas. Pathol Oncol Res. 1996;2:229-236. 223. Folberg R, Mehaffey M, Gardner LM, Meyer M, Rummelt V, Pe’er J. The microcirculation of choroidal and ciliary body melanomas. Eye. 1997;11:227-238. 224. Spire M, Devouassoux MS, Kodjikian L, Janin-Magnificat H, Fleury J, Grange JD. Primary transpupillary thermotherapy for 18 small posterior pole uveal melanomas. Am J Ophthalmol. 2006;141:840-849. 225. Mueller AJ, Freeman WR, Schaller UC, Kampik A, Folberg R. Complex microcirculation patterns detected by confocal indocyanine green angiography predict time to growth of small choroidal melanocytic tumors: MuSIC Report II. Ophthalmology. 2002;109:2207-2214. 226. Buerk BM, Pulido JS, Chiong I, et al. Vascular perfusion of choroidal melanoma by 3.0 tesla magnetic resonance imaging. Trans Am Ophthalmol Soc. 2004;102:209-215.

227. Lee ES, Baratz KH, Pulido JS, Salomao DR. Expression of vascular endothelial growth factor in iris melanoma. Arch Ophthalmol. 2006;124:13491350. 228. Nordlund JR, Robertson DM, Herman DC. Ultrasound biomicroscopy in management of malignant iris melanoma. Arch Ophthalmol. 2003;121:725727. 229. Geisse LJ, Robertson DM. Iris melanomas. Am J Ophthalmol. 1985;99:638-648. 230. Conway RM, Chua WC, Qureshi C, Billson FA. Primary iris melanoma: diagnostic features and outcome of conservative surgical treatment. Br J Ophthalmol. 2001;85:848-854. 231. Autier P, Dore JF, Reis AC, et al. Sunscreen use and intentional exposure to ultraviolet A and B radiation: a double blind randomized trial using personal dosimeters. Br J Cancer. 2000;83:1243-1248. 232. Umeda M, Komatsubara H, Shibuya Y, Yokoo S, Komori T. Premalignant melanocytic dysplasia and malignant melanoma of the oral mucosa. Oral Oncol. 2002;38:714-722. 233. Cohen Y, Rosenbaum E, Begum S, et al. Exon 15 BRAF mutations are uncommon in melanomas arising in nonsun-exposed sites. Clin Cancer Res. 2004;10:3444-3447. 234. Wong CW, Fan YS, Chan TL, et al, Cancer Genome Project. BRAF and NRAS mutations are uncommon in melanomas arising in diverse internal organs. J Clin Pathol. 2005;58:640-644. 235. Edwards RH, Ward MR, Wu H, et al. Absence of BRAF mutations in UV-protected mucosal melanomas. J Med Genet. 2004;41:270-272. 236. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135-2147. 237. Muchmore JH, Mizuguchi RS, Lee C. Malignant melanoma in American black females: an unusual distribution of primary sites. J Am Coll Surg. 1996;183:457-465. 238. Takagi M, Ishikawa G, Mori W. Primary malignant melanoma of the oral cavity in Japan: with special reference to mucosal melanosis. Cancer. 1974;34:358-370. 239. Rogers RS III, Gibson LE. Mucosal, genital, and unusual clinical variants of melanoma. Mayo Clin Proc. 1997;72:362-366. 240. Liang KV, Sanderson SO, Nowakowski GS, Arora AS. Metastatic malignant melanoma of the gastrointestinal tract. Mayo Clin Proc. 2006;81:511516. 241. Hicks MJ, Flaitz CM. Oral mucosal melanoma: epidemiology and pathobiology. Oral Oncol. 2000;36:152-169. 242. Wada H, Nemoto K, Ogawa Y, et al. A multi-institutional retrospective analysis of external radiotherapy for mucosal melanoma of the head and neck in Northern Japan. Int J Radiat Oncol Biol Phys. 2004;59:495-500. 243. Yeh JJ, Weiser MR, Shia J, Hwu WJ. Response of stage IV anal mucosal melanoma to chemotherapy. Lancet Oncol. 2005;6:438-439. 244. Kim KB, Sanguino AM, Hodges C, et al. Biochemotherapy in patients with metastatic anorectal mucosal melanoma. Cancer. 2004;100:1478-1483. 245. Flaherty KT, Brose M, Schuchter L, et al. Phase I/II trial of BAY 439006, carboplatin (C) and paclitaxel (P) demonstrates preliminary antitumor activity in the expansion cohort of patients with metastatic melanoma [abstract]. J Clin Oncol. 2004;22(suppl):711s. Abstract 7507. 246. Chang P, Knapper WH. Metastatic melanoma of unknown primary. Cancer. 1982;49:1106-1111. 247. Dasgupta T, Bowden L, Berg JW. Malignant melanoma of unknown primary origin. Surg Gynceol Obstet. 1963;117:341-345. 248. Schlagenhauff B, Stroebel W, Ellwanger U, et al. Metastatic melanoma of unknown primary origin shows prognostic similarities to regional metastatic melanoma: recommendation for initial staging examinations. Cancer. 1997; 80:60-65. 249. Ross MI, Cormier JN, Xing Y, Gershenwald JE, Lee JE, Mansfield PF. Prognosis and survival outcomes in melanoma patients with unknown primary site (MUP) [abstract]. J Clin Oncol. 2004;22(suppl):721s. Abstract 7544. 250. Baab GH, McBride CM. Malignant melanoma: the patient with an unknown site of primary origin. Arch Surg. 1975;110:896-900. 251. Anbari KK, Schuchter LM, Bucky LP, et al, University of Pennsylvania Pigmented Lesion Study Group. Melanoma of unknown primary site: presentation, treatment, and prognosis: a single institution study. Cancer. 1997;79: 1816-1821. 252. Wong JH, Cagle LA, Morton DL. Surgical treatment of lymph nodes with metastatic melanoma from unknown primary site. Arch Surg. 1987;122: 1380-1383. 253. Kole AC, Nieweg OE, Pruim J, et al. Detection of unknown occult primary tumors using positron emission tomography. Cancer. 1998;82:11601166.

The Symposium on Solid Tumors will continue in the May issue. Mayo Clin Proc.

•

April 2007;82(4):490-513

•

www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

513